| tramadol |
serotonin-receptor |
True Positive |
16296359 |
Mimami K: [Recent evidences in the pharmacological mechanisms of the tramadol] . Masui. 2005 Nov;54(11):1224-33. Tramadol [(1R, 2R) and (1S, 2S)-2-dimethyl-amino-methyl-1-(3-methoxyphenyl) -cyclohexanol hydrochloride] has been used clinically. It binds to micro-opioid receptors with lower affinity than morphine, which suggests that the antinociceptive action of tramadol may not be due to opioid receptor binding. Several lines of evidence have shown that tramadol inhibits the reuptake of monoamines, as do antidepressant drugs such as desipramine. Tramadol inhibits the reuptake of NE and serotonin. The mechanisms of action of tramadol have not been well understood. Recently, some evidences in the mechanisms of action of tramadol have been published. Tramadol inhibits the muscarinic receptor, serotonin receptor, and nicotinic acetylcholine receptor ion-channel, suggesting these receptors might be related to the mechanisms of action of tramadol. In this review, the mechanisms of action of tramadol were reviewed form these findings. Tramadol does not alter renal blood flow (RBF) in normal rats. This suggests that tramadol would be a safe analgesic maintaining RBF during the postoperative period. It would be necessary to study the effects of tramadol on orphan G-ptotein coupled receptor which is related to the pain. |
| tramadol |
glycine-receptors |
False Positive |
15845694 |
Hara K, Minami K, Sata T: The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg. 2005 May;100(5):1400-5 We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadol's action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid (A) (GABA (A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA (A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA (A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations. |
| tramadol |
IL-2-receptor |
False Positive |
16171665 |
Wang G, Weng Y, Ishiguro Y, Sakamoto H, Morita S: The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J Clin Anesth. 2005 Sep;17(6):444-50. STUDY OBJECTIVE: To investigate the effect of tramadol on the production of serum interleukin (IL) 6, IL-10, and IL-2 and soluble (s) IL-2 receptor (R), thereby evaluating its effects on the proinflammatory and anti-inflammatory responses and immune function in cancer patients undergoing conventional pulmonary lobectomy. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II adult patients scheduled for conventional pulmonary lobectomy. INTERVENTIONS: Patients were randomly divided into 2 groups (n = 20 in each group). Both groups received general anesthesia with enflurane combined with epidural blockade. At 5 minutes before skin incision, patients were given either tramadol 1.5 mg/kg intravenously (IV), followed by a continuous infusion of 0.5 mg/kg per hour until the end of surgery (group I), or IV normal saline (group II). MEASUREMENTS AND MAIN RESULTS: Venous blood samples for the measurement of serum cytokine concentrations were taken before anesthesia and at set intervals until 24 hours after operation. Serum levels of IL-6 and IL-10 in both groups were increased significantly during and after operation compared with baseline levels (P < .05). No statistical differences between groups in terms of IL-6 and IL-10 were observed. Levels of IL-2 were elevated significantly at 4 hours after operation in group I as compared with baseline levels (P < .001), whereas they remained low at 4 and 24 hours after operation in group II (P < .01). There were significant increases in levels of sIL-2R at 4 and 24 hours after operation in group II as compared with baseline levels (P < .05) and at 24 hours after operation in group I (P < .01). Levels of IL-2 were higher at 4 and 24 hours after operation in group I than in group II (P < .01). Levels of sIL-2R were lower at 4 hours after operation in group I than in group II (P < .01). CONCLUSIONS: IV infusion of tramadol does not seem to alter IL-6/IL-10 cytokine response to pulmonary lobectomy. As tramadol was associated with increased IL-2 and delayed enhancement of sIL-2R in our study, it may attenuate to some extent an impaired immune response in pulmonary lobectomy. |
| tramadol |
phosphoenolpyruvate-carboxykinase |
True Positive |
11723065 |
Cheng JT, Liu IM, Chi TC, Tzeng TF, Lu FH, Chang CJ: Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001 Dec;50(12):2815-21. The effect of tramadol on the plasma glucose level of streptozotocin (STZ)-induced diabetic rats was investigated. A dose-dependent lowering of plasma glucose was seen in the fasting STZ-induced diabetic rats 30 min after intravenous injection of tramadol. This effect of tramadol was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptors. However, response to tramadol was not changed in STZ-induced diabetic rats receiving p-chlorophenylalanine at a dose sufficient to deplete endogenous 5-hydroxytrptamine (5-HT). Therefore, mediation of 5-HT in this action of tramadol is ruled out. In isolated soleus muscle, tramadol enhanced the uptake of radioactive glucose in a concentration-dependent manner. The stimulatory effects of tramadol on glycogen synthesis were also seen in hepatocytes isolated from STZ-induced diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid mu-receptors. The mRNA and protein levels of the subtype 4 form of glucose transporter in soleus muscle were increased after repeated treatments for 4 days with tramadol in STZ-induced diabetic rats. Moreover, similar repeated treatments with tramadol reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase in the liver of STZ-induced diabetic rats. These results suggest that activation of opioid mu-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin. |
| tramadol |
COPD |
False Positive |
11218788 |
Larsen J, Arnberg A, Brosen K: [Tramadol and oxazepam. Ugeskr Laeger. 2001 Jan 22;163(4):458-60. Effect on pulmonry function in elderly patients with chronic obstructive lung disease]. Many patients with chronic obstructive pulmonary disease (COPD) suffer from osteoporotic pain as a result of glucocorticoid treatment and nervous symptoms partly related to their lung disease. There seems to be som reluctance to treat these patients with an opioid or benzodiazepine. Upon request, the Drug Information Centre in Odense made an extensive literature search on the subject. No documentation was found that tramadol additionally depresses the respiration in patients with COPD, nor has oxazepam in clinically relevant doses been found to exacerbate their lung disease. The clinical effect is subject to large interindividual variability, and the use of these drugs should, to a greater extent, rest on experience with the individual patient. There seems to be no reason to maintain a priori this rigoristic reluctance to use tramadol and/or oxazepam in patients with COPD. |
| tramadol |
COX-1 |
True Positive |
11124014 |
Buccellati C, Sala A, Ballerio R, Bianchib M: Tramadol anti-inflammatory activity is not related to a direct inhibitory action on prostaglandin endoperoxide synthases. Eur J Pain. 2000;4(4):413-5. The analgesic drug tramadol has been shown to relieve pain in inflammatory conditions, to inhibit the development of experimental inflammation, and to reduce prostaglandin (PG) E (2) concentrations in the inflammatory exudate. In this study, we evaluated the putative activity of tramadol to suppress prostaglandin endoperoxide synthase-1 (PGHS-1), and prostaglandin endoperoxide synthase-2 (PGHS-2) activities in human whole blood in vitro. Platelet thromboxane (Tx) B (2) production and monocyte PGE (2) production in LPS- stimulated blood were measured in samples incubated with different concentrations (300 ng/ml, 3 microg/ml, 30 microg/ml) of tramadol or its enantiomers. Neither tramadol nor the enantiomers inhibited the formation of arachidonic acid metabolites. Our results indicate that the anti-inflammatory effect of tramadol demonstrated in some models is not related to a direct inhibitory effect on the formation of prostanoids. |
| tramadol |
insulin |
True Positive |
16140165 |
Choi SB, Jang JS, Park S: Tramadol enhances hepatic insulin sensitivity via enhancing insulin signaling cascade in the cerebral cortex and hypothalamus of 90% pancreatectomized rats. Brain Res Bull. 2005 Sep 30;67(1-2):77-86. Clinical observation found that tramadol, mu opioid receptor (MOR) agonist and serotonin (5-HT) reuptake inhibitor, has a hypoglycemic effect in type 2 diabetes patients. The mechanism of its hypoglycemic effect has not been fully defined. This study showed that tramadol activated a neuronal insulin signaling cascade by increasing the induction of insulin receptor substrate-2 expression in primary cultured neuronal cells while this activation was suppressed by naloxone (MOR inhibitor) and dexamethasone (non-specific inhibitor of MOR and 5-HT receptor, DEX). Glucose utilization of the cerebral cortex and hypothalamus was enhanced by a 4-week-tramadol administration in 90% pancreatectomized rats, in vivo, as assessed by measurement of glucokinase expression and glycogen deposition via activating insulin signaling cascade such as neuronal cells in vitro. This improvement was almost completely suppressed by naloxone as well as DEX. Tramadol decreased fasted serum glucose levels, favored an increase in the glucose infusion rate and reduced endogeneous hepatic glucose production after 4 weeks of treatment. However, tramadol did not modulate hepatic glucose output directly, as exhibited by liver perfusion, suggesting tramadol altered hepatic glucose utilization through the effect of organs other than the liver, possibly the central nervous system. The data suggest that tramadol ameliorates peripheral glucose metabolism through central activation of MOR, and that central and peripheral glucose metabolism are therefore likely to be interrelated. |
| tramadol |
insulin |
True Positive |
11723065 |
Cheng JT, Liu IM, Chi TC, Tzeng TF, Lu FH, Chang CJ: Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001 Dec;50(12):2815-21. The effect of tramadol on the plasma glucose level of streptozotocin (STZ)-induced diabetic rats was investigated. A dose-dependent lowering of plasma glucose was seen in the fasting STZ-induced diabetic rats 30 min after intravenous injection of tramadol. This effect of tramadol was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptors. However, response to tramadol was not changed in STZ-induced diabetic rats receiving p-chlorophenylalanine at a dose sufficient to deplete endogenous 5-hydroxytrptamine (5-HT). Therefore, mediation of 5-HT in this action of tramadol is ruled out. In isolated soleus muscle, tramadol enhanced the uptake of radioactive glucose in a concentration-dependent manner. The stimulatory effects of tramadol on glycogen synthesis were also seen in hepatocytes isolated from STZ-induced diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid mu-receptors. The mRNA and protein levels of the subtype 4 form of glucose transporter in soleus muscle were increased after repeated treatments for 4 days with tramadol in STZ-induced diabetic rats. Moreover, similar repeated treatments with tramadol reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase in the liver of STZ-induced diabetic rats. These results suggest that activation of opioid mu-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin. |
| tramadol |
Monoamine-oxidase |
False Positive |
305247 |
Osterloh G, Friderichs E, Felgenhauer F, Gunzler WA, Henmi Z, Kitano T, Nakamura M, Hayashi H, Ishii I: [General pharmacological studies on tramadol, a potent analgetic agent (author's transl)]. Arzneimittelforschung. 1978;28(1a):135-51. The general pharmacological properties of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal) are described and compared with those of other strong narcotic analgetics. In behavioral studies tramadol in high doses had a primarily stimulating effect in mice and rats and a sedative effect in rabbits and dogs. The Straub tail phenomenon, a reaction typical for mice administered morphine, was observed only after subtoxic doses of tramadol. In i.v. doses tramadol generally caused a weak central inhibition of non-stimulated and electrically stimulated brain activity in unanesthetized rabbits. Muscle tone and motor coordination in rats and mice were only slightly affected by the drug, in contrast to the effect of morphine. Unlike other strong analgesics tramadol in doses of 5--20 mg/kg i.v. did not cause respiratory depression and even clearly increased respiratory volume and rate in conscious rabbits and anesthetized dogs. In cats and dogs i.v. doses of tramadol up to 10 mg/kg were well tolerated in the cardiovascular system. Tramadol has a slight, papaverine-like spasmolytic effect and no effect on gastrointestinal motility or urinary and electrolyte excretion. The drug showed no antipyretic properties in rabbits. It inhibited edema in rats and guinea pigs but had no antiproliferative effect in the cotton pellet test in rats. Tramadol did not inhibit monoamine oxidase activity or cause enzyme induction in the rat liver. |
| tramadol |
NMDA-receptor |
True Positive |
15845694 |
Hara K, Minami K, Sata T: The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg. 2005 May;100(5):1400-5 We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadol's action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid (A) (GABA (A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA (A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA (A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations. |
| tramadol |
brain-derived-neurotrophic-factor |
False Positive |
15464068 |
Faron-Gorecka A, Kusmider M, Inan SY, Siwanowicz J, Piwowarczyk T, Dziedzicka-Wasylewska M: Long-term exposure of rats to tramadol alters brain dopamine and alpha 1-adrenoceptor function that may be related to antidepressant potency. Eur J Pharmacol. 2004 Oct 6;501(1-3):103-10. The aim of the present study was to determine whether tramadol, which has a potential antidepressant efficacy, evokes, when administered repeatedly, changes similar to the alterations induced by conventional antidepressant drugs. Repeated administration of tramadol (20 mg/kg i.p. for 21 days) enhanced the d-amphetamine-induced locomotor hyperactivity and increased the density of alpha (1)-adrenoceptors in the rat brain cortex, as measured by saturation analysis of [(3) H] prazosin binding. Autoradiographic analysis of [(3) H] 7-OH-DPAT and [(3) H] raclopride binding revealed a significant up-regulation of dopamine D2 and D3 receptors in the rat nucleus accumbens upon repeated treatment with tramadol. All the above-mentioned effects induced by repeated administration of tramadol resemble the effects induced by conventional antidepressants. However, tramadol when administered repeatedly did not increase the levels of mRNA encoding for brain-derived neurotrophic factor (BDNF) and its receptor, TrkB. This is what differs tramadol from conventional antidepressants, since neurotrophic effects of these drugs have recently been postulated. |
| tramadol |
5-HT1A |
True Positive |
17393145 |
Berrocoso E, De Benito MD, Mico JA: Role of serotonin 5-HT (1A) and opioid receptors in the antiallodynic effect of tramadol in the chronic constriction injury model of neuropathic pain in rats. Psychopharmacology. 2007 Jul;193(1):97-105. Epub 2007 Mar 29. RATIONALE: Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms. OBJECTIVES: The present study was undertaken to evaluate the potential role of 5-HT (1A) receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT (1A) receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT (1A) receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats. RESULTS: The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5-10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg). CONCLUSIONS: These findings suggest the involvement of opioid and 5-HT (1A) receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT (1A) antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain. |
| tramadol |
5-HT1A |
True Positive |
16832657 |
Berrocoso E, Rojas-Corrales MO, Mico JA: Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice. Psychopharmacology. 2006 Sep;188(1):111-8. Epub 2006 Jul 11. RATIONALE: Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to i-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. OBJECTIVES: The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol. METHODS: The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1' -biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. RESULTS: The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. CONCLUSIONS: These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated. |
| tramadol |
5-HT1A |
True Positive |
16730359 |
Berrocoso E, Mico JA, Ugedo L: In vivo effect of tramadol on locus coeruleus neurons is mediated by alpha2-adrenoceptors and modulated by serotonin. Neuropharmacology. 2006 Jul;51(1):146-53. Epub 2006 May 30. Tramadol is a centrally-acting analgesic endowed with opioid, noradrenergic and serotonergic properties. Various data suggest that, in addition to its analgesic effect, tramadol may have antidepressant and anxiolytic-like effects. This study investigates, through single-unit extracellular recording techniques, the in vivo effects of tramadol on locus coeruleus (LC) neurons and its possible effects on alpha (2)-adrenoceptors, opioid receptors and the 5-HT system. Tramadol produced a dose-dependent and complete inhibition of LC activity (ED (50)=2.1mg/kg). This inhibitory effect was prevented and reversed by the selective alpha (2)-adrenoceptor antagonist, idazoxan, but not by the opioid receptor antagonist, naloxone. The inhibition of the synthesis of 5-HT by p-chlorophenylalanine and the pre-administration of the 5-HT (1A) receptor agonist, 8-OH-DPAT at 40microg/kg, caused a significant potentiation of the tramadol effect decreasing the ED (50) by 53% and 67% respectively. Lower doses of 8-OH-DPAT, of 1 and 4microg/kg, did not significantly modify the tramadol effect. In summary, the results indicate that tramadol elicits an inhibitory effect on LC neurons in vivo through alpha (2)-adrenoceptors. Moreover, this effect is modulated by the 5-HT system and particularly by 5-HT (1A) receptors. |
| tramadol |
5-HT1A |
True Positive |
15777775 |
Rojas-Corrales MO, Berrocoso E, Mico JA: Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol. Eur J Pharmacol. 2005 Mar 21;511(1):21-6. Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) in the raphe nucleus. We have previously demonstrated that pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine (1A/1B) receptor antagonist, enhanced tramadol antinociception and that the selective 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) reduced it. These effects were related to the negative feedback control that regulates raphe region neurones. The current study examines the ability of the selective antagonist at somatodendritic 5-HT1A receptors, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY100635, 0.8 mg/kg), the selective antagonist at terminal 5-HT1B receptors, N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1' -biphenyl)-4-carboxamide (SB216641, 0.1-0.8 mg/kg) and the selective agonist at 5-HT1B receptors, 1,4-tDihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b] pyridin-5-one (CP93129, 0.2-0.4 mg/kg), to modify the antinociceptive effect of 4-64 mg/kg of tramadol in the hot plate test in mice. The results show that 0.8 mg/kg of WAY100635 enhanced antinociceptive effect of tramadol while neither agonism nor antagonism at the 5-HT1B receptor modifies it significantly at the doses tested. These results account for involvement of the somatodendritic 5-HT1A receptors in the analgesic effect of tramadol and support the supraspinal interaction of serotonin and the opioid system in the regulation of pain. |
| tramadol |
5-HT1A |
True Positive |
14970364 |
Houlihan DJ: Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother. 2004 Mar;38(3):411-3. Epub 2004 Jan 23. OBJECTIVE: To report a case of serotonin syndrome (SS) resulting from the addition of tramadol to a medication regimen of venlafaxine and mirtazapine. CASE SUMMARY: A 47-year-old white man receiving combined mirtazapine and venlafaxine therapy for major depressive disorder developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever on coadministration of tramadol for chronic pain. An objective causality assessment revealed that the addition of tramadol was the probable cause of the adverse reaction. DISCUSSION: SS is a potentially fatal iatrogenic complication of serotonergic polypharmacy. Considered idiopathic in presentation, it typically appears after initiation or dose escalation of the offending agent to a regimen including other serotonergic agents. All drugs that directly or indirectly increase central serotonin neurotransmission at postsynaptic 5-HT (1A) and 5-HT (2A) receptors can produce SS. Individual vulnerability appears to play a role in the development of SS. It is likely that the activation of 5-HT (1A) receptors by mirtazapine, the combined serotonin reuptake inhibition by venlafaxine and tramadol, as well as possible serotonin release by tramadol, contributed to the development of SS in this case. CONCLUSIONS: It is vital that clinicians are aware of the potential for SS when psychotropic and nonpsychotropic agents are coadministered to certain patients, such as those with both depression and chronic pain. |
| tramadol |
5-HT1A |
True Positive |
11050366 |
Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, Roca-Vinardell A, Mico JA: Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine (1A/1B) antagonist, enhances the analgesic effect of tramadol. Pain. 2000 Nov;88(2):119-24. The ability of pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine (1A/1B) antagonist, to enhance the clinical antidepressant response to selective serotonin re-uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally-acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re-uptake of 5-HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non-effective acute dose of tramadol (10-40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (+/-) 8-OH-DPAT (0.125-1 mg/kg, s.c.), a selective 5-HT (1A) agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5-HT (1A) receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound. |
| tramadol |
5-HT1A |
True Positive |
8955860 |
Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung. 1996 Nov;46(11):1029-36. In in vitro receptor binding and synaptosomal uptake experiments the (+)-enantiomer of tramadol (CAS 148229-78-1) is specific for the mu-opioid receptor site and for the serotonin (5-HT) carrier, whereas the (-)-enantiomer (CAS 148229-79-2) has a higher affinity to the noradrenaline (NA) transporter. The antinociceptive active tramadol metabolite O-demethyltramadol (M1) shows a pronounced mu-selectivity. With respect to in vitro receptor binding experiments, the affinity of (+)-M1 to this opioid receptor subtype is more than two orders of magnitude higher than that of (+)-tramadol and approximately 1/10 that of morphine. Tramadol and M1 (and the enantiomers thereof) have no affinity to other receptor or uptake sites tested, e.g. 5-HT1A, 5-HT2, 5-HT3, NMDA (ligand: MK801), dopamine (DA)-D1, DA-D2, benzodiazepine, muscarine M1 and DA uptake (Ki > or = 2 x 10 (-5) mol/l). Ex vivo neurotransmitter determinations show that tramadol (46.4 mg/kg i.p.) elevates the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid and enhances DA release in definite brain areas. The active enantiomer of the racemic tramadol is the (+)-enantiomer. (+)-Tramadol significantly enhances the turnover rate of DA. The enantioselective elevation of DOPAC by (+)-tramadol is antagonized by naloxone (2 x 5 mg/kg i.p.). Morphine (21.5 mg/kg i.p.) enhances the turnover of NA in definite brain areas. Neither the NA-specific uptake inhibition nisoxetine (31.6 mg/kg i.p.) nor tramadol (or its (+)- and (-)-enantiomers) have any influence on the NA turnover. Tramadol reduces the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Morphine enhances, whereas tramadol reduces, 5-HT utilisation in the brain areas under assay. The 5-HT specific uptake inhibitor fluoxetine (20 mg/kg i.p.) shows the same influence on 5-HT turnover as tramadol. The results indicate that tramadol enhances DA turnover via an opioid mechanism. The interaction with the noradrenergic and serotonergic neurotransmission is clearly different from that of an opioid receptor agonist and closely resembles that of NA and 5-HT uptake inhibitors. |
| tramadol |
G-protein-coupled-receptor |
True Positive |
16679816 |
Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A: The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes. Pharmacology. 2006;77(2):93-9. Epub 2006 May 5. PURPOSE: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT (2C) R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT (2C) R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT (2C) R expressed in Xenopus oocytes. METHODS: We examined the effect of O-desmethyl tramadol on 5-HT (2C) R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3) H] 5-HT by 5-HT (2C) R. RESULTS: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca (2+)-activated Cl (-) currents in oocytes that expressed 5-HT (2C) R. The inhibitory effect of O-desmethyl tramadol on 5-HT (2C) R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3) H] 5-HT by 5-HT (2C) R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3) H] 5-HT by 5-HT (2C) R without changing maximum binding, which indicated competitive inhibition. CONCLUSION: These results suggest that O-desmethyl tramadol inhibits 5-HT (2C) R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol. |
| tramadol |
CYP2D |
True Positive |
8272795 |
Collart L, Luthy C, Favario-Constantin C, Dayer P: [Duality of the analgesic effect of tramadol in humans] . Schweiz Med Wochenschr. 1993 Nov 27;123(47):2241-3. Tramadol is a central analgesic with low affinity for opioid receptors. A major active metabolite (O-desmethyl-tramadol) shows a higher affinity for opioid receptors than tramadol. The influence of naloxone and quinidine (a selective P450DB1 or CAP2D6 inhibitor) on tramadol effect was investigated crossover and double-blind vs placebo in healthy subjects. They received tramadol (100 mg p.o.), tramadol+naloxone (0.8 mg i.v.) and tramadol+quinidine (50 mg p.o.). Analgesia was assessed, after transcutaneous electrical stimulation, by a categorical numerical scale and by measurement of the antinociceptive effect at spinal level by R-III reflex. Analgesia peaked at 3 hours and lasted about 6 hours. The mean decrease in peak tramadol analgesia by naloxone was only 31%. Quinidine had no effect on the extent of tramadol analgesia, but inhibited tramadol induced myosis. We therefore conclude that tramadol analgesia is only partially mediated by a mu opioid agonist effect. Tramadol analgesia thus results from an action on opioid receptors other than the mu subtype and/or from nonopioid effects (monoaminergic system). Quinidine blockade of tramadol myosis suggests that the mu agonist component of tramadol effect results from its O-demethylation by the polymorphic P450DB1 enzyme. |
| tramadol |
5-HT-2A |
False Positive |
12079682 |
Oliva P, Aurilio C, Massimo F, Grella A, Maione S, Grella E, Scafuro M, Rossi F, Berrino L: The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol. 2002 Jun 12;445(3):179-85. The aim of this study was to investigate the neurotransmissions involved in the antinociceptive effect of tramadol in the formalin test, which is an animal model of acute and tonic pain. A subcutaneous injection of formalin produces a biphasic nociceptive response: phase 1 (0-10 min-acute pain) and phase 2 (21-60 min-tonic pain). Nociceptive activity is reduced greatly during the 10 min between these two phases. We measured in mice the effects of (+/-)-tramadol, and of (+)- and (-)-tramadol administered before the induction of pain by formalin, in the presence and absence of drugs that act on the opioidergic, serotonergic and noradrenergic systems (naloxone, ketanserin, fluoxetine, maprotiline). With respect to animals treated with formalin alone, (+/-)-tramadol and its enantiomers significantly reduced the duration of nociceptive behaviours (lifting, licking, favouring, shaking, and flinching of the formalin-treated paw) during phase 2. This effect was prevented by the 5-HT (2) receptor antagonist ketanserin, but not by naloxone which, on the contrary, was able to prevent the antinociceptive effect of morphine. Naloxone and ketanserin did not affect the duration of nociceptive behaviour in animals not treated with tramadol. Fluoxetine (a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor), but not maprotiline (a selective norepinephrine reuptake inhibitor), potentiated the antinociceptive effect of (+/-)-tramadol. In conclusion, we demonstrate that the serotonergic pathway is responsible for the antinociceptive effect of tramadol in phase 2 of the formalin test, and that this effect is mediated by 5-HT (2) receptors. |
| tramadol |
5-HT-2A |
False Positive |
11565620 |
Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA: Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function. J Psychopharmacol. 2001 Sep;15(3):147-53. The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H] dihydroalprenolol and [3H] ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphe (DRN) or median raphe (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology. |
| tramadol |
lactate-dehydrogenase |
False Positive |
15886461 |
Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U: Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci. 2005 Mar;30(2):245-52. In this study, histopathological and biochemical changes due to chronic usage of morphine or tramadol in liver and kidney were assessed in rats. Thirty male Wistar rats (180-220 g) were included and divided into three groups. Normal saline (1 ml) was given intraperitoneally as placebo in the control group (n = 10). Morphine group (n = 10) received morphine intraperitoneally at a dose of 4, 8, 10 mg/kg/day in the first, second and the third ten days of the study, respectively. Tramadol group (n = 10), received the drug intraperitoneally at doses of 20, 40 and 80 mg/kg/day in the first, second and the third ten days of the study, respectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinin, blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were measured in the serum. Liver and kidney specimens were evaluated by light microscopy. Serum ALT, AST, LDH, BUN and creatinin levels were significantly higher in morphine group compared to the control group. Serum LDH, BUN and creatinin levels were significantly increased in the morphine group compared to the tramadol group. The mean MDA level was significantly higher in morphine group compared to the tramadol and control groups (P < 0.05). Light microscopy revealed severe centrolobular congestion and focal necrosis in the liver of morphine and tramadol groups, but perivenular necrosis was present only in the morphine group. The main histopathologic finding was vacuolization in tubular cells in morphine and tramadol groups. Our findings pointed out the risk of increased lipid peroxidation, hepatic and renal damage due to long term use of opioids, especially morphine. Although opioids are reported to be effective in pain management, their toxic effects should be kept in mind during chronic usage. |
| tramadol |
5-hydroxytryptamine-receptors |
True Positive |
17380034 |
Minami K, Uezono Y, Ueta Y: Pharmacological aspects of the effects of tramadol on G-protein coupled receptors. J Pharmacol Sci. 2007 Mar;103(3):253-60. Tramadol is an analgesic that is used worldwide, but its mechanisms of action have not been elucidated. It has been speculated that tramadol acts primarily through the activation of micro-opioid receptors and the inhibition of monoamine reuptake. The majority of studies to date have focused on ion channels in the central nervous system as targets of anesthetics and analgesics. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for analgesics and anesthetics. In particular, tramadol has been shown to affect GPCRs, including muscarinic acetylcholine receptors and 5-hydroxytryptamine receptors. Here, the effects of tramadol on monoamine transporters, GPCRs, and ion channels are presented, and recent research on the pharmacology of tramadol is discussed. |
| tramadol |
5-hydroxytryptamine-receptors |
True Positive |
15305853 |
KuKanich B, Papich MG: Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther. 2004 Aug;27(4):239-46. Tramadol is an analgesic and antitussive agent that is metabolized to O-desmethyltramadol (M1), which is also active. Tramadol and M1 exert their mode of action through complex interactions between opiate, adrenergic, and serotonin receptors. The pharmacokinetics of tramadol and M1 were examined following intravenous and oral tramadol administration to six healthy dogs, as well as intravenous M1 to three healthy dogs. The calculated parameters for half-life, volume of distribution, and total body clearance were 0.80 +/- 0.12 h, 3.79 +/- 0.93 L/kg, and 54.63 +/- 8.19 mL/kg/min following 4.4 mg/kg tramadol HCl administered intravenously. The systemic availability was 65 +/- 38% and half-life 1.71 +/- 0.12 h following tramadol 11 mg/kg p.o. M1 had a half-life of 1.69 +/- 0.45 and 2.18 +/- 0.55 h following intravenous and oral administration of tramadol. Following intravenous M1 administration the half-life, volume of distribution, and clearance of M1 were 0.94 +/- 0.09 h, 2.80 +/- 0.15 L/kg, and 34.93 +/- 5.53 mL/kg/min respectively. Simulated oral dosing regimens at 5 mg/kg every 6 h and 2.5 mg/kg every 4 h predict tramadol and M1 plasma concentrations consistent with analgesia in humans; however, studies are needed to establish the safety and efficacy of these doses. |
| tramadol |
IL-2 |
True Positive |
16171665 |
Wang G, Weng Y, Ishiguro Y, Sakamoto H, Morita S: The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J Clin Anesth. 2005 Sep;17(6):444-50. STUDY OBJECTIVE: To investigate the effect of tramadol on the production of serum interleukin (IL) 6, IL-10, and IL-2 and soluble (s) IL-2 receptor (R), thereby evaluating its effects on the proinflammatory and anti-inflammatory responses and immune function in cancer patients undergoing conventional pulmonary lobectomy. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II adult patients scheduled for conventional pulmonary lobectomy. INTERVENTIONS: Patients were randomly divided into 2 groups (n = 20 in each group). Both groups received general anesthesia with enflurane combined with epidural blockade. At 5 minutes before skin incision, patients were given either tramadol 1.5 mg/kg intravenously (IV), followed by a continuous infusion of 0.5 mg/kg per hour until the end of surgery (group I), or IV normal saline (group II). MEASUREMENTS AND MAIN RESULTS: Venous blood samples for the measurement of serum cytokine concentrations were taken before anesthesia and at set intervals until 24 hours after operation. Serum levels of IL-6 and IL-10 in both groups were increased significantly during and after operation compared with baseline levels (P < .05). No statistical differences between groups in terms of IL-6 and IL-10 were observed. Levels of IL-2 were elevated significantly at 4 hours after operation in group I as compared with baseline levels (P < .001), whereas they remained low at 4 and 24 hours after operation in group II (P < .01). There were significant increases in levels of sIL-2R at 4 and 24 hours after operation in group II as compared with baseline levels (P < .05) and at 24 hours after operation in group I (P < .01). Levels of IL-2 were higher at 4 and 24 hours after operation in group I than in group II (P < .01). Levels of sIL-2R were lower at 4 hours after operation in group I than in group II (P < .01). CONCLUSIONS: IV infusion of tramadol does not seem to alter IL-6/IL-10 cytokine response to pulmonary lobectomy. As tramadol was associated with increased IL-2 and delayed enhancement of sIL-2R in our study, it may attenuate to some extent an impaired immune response in pulmonary lobectomy. |
| tramadol |
IL-2 |
True Positive |
9313273 |
Sacerdote P, Bianchi M, Manfredi B, Panerai AE: Effects of tramadol on immune responses and nociceptive thresholds in mice. Pain. 1997 Sep;72(3):325-30. Tramadol is a centrally acting analgesic drug with a dual mechanism of action: binding to mu-opioid receptors and potentiation of the monoaminergic systems. In this study, we evaluated the effects of the acute and chronic administration of tramadol on nociceptive thresholds (by the hot-plate test) and on immune responses (by measuring Concanavalin A-induced splenocyte proliferation, IL-2 production and natural killer activity) in the mouse. After acute subcutaneous administration, tramadol induced antinociception starting from a dose of 20 mg/kg, whereas it significantly enhanced natural killer activity and IL-2 production at doses as low as 1 mg/kg and splenocyte proliferation starting from a dose of 10 mg/kg. After the chronic administration, the antinociceptive effect of the drug was still present, whereas the immune modifications disappeared. Thus, the pharmacological profile of tramadol is totally different from that of other drugs which bind mu-opioid receptors. Our results suggest that tramadol could be a good choice for the treatment of pain in patients where immunosuppression may be particularly contraindicated. |
| tramadol |
CMAP |
False Positive |
12598263 |
Jou IM, Chu KS, Chen HH, Chang PJ, Tsai YC: The effects of intrathecal tramadol on spinal somatosensory-evoked potentials and motor-evoked responses in rats. Anesth Analg. 2003 Mar;96(3):783-8 Tramadol has been proven to exert a local anesthetic-type effect on peripheral nerves in both clinical and laboratory studies. In this study, we evaluated the effects of tramadol on sensory and motor neural conduction when administered intrathecally in the rat. Tramadol (0, 1, or 2 mg) was administered through an intrathecal catheter. Spinal somatosensory-evoked potentials (SSEPs) were recorded at the thoracolumbar junction after stimulation of the sciatic nerve. An evoked compound muscle action potential (CMAP) was recorded in the intrinsic muscles of the foot in response to electric stimulation of the lower thoracic (T1213) interspinous space. Both SSEP and CMAP were obtained before drug application as the pretreatment baseline and at 5, 15, and 30 min after treatment, and at 30- or 60-min intervals thereafter for another 4.5 h. SSEP was averaged from 20 responses, whereas CMAP was obtained from a single stimulation. Reproducible SSEPs and CMAP were consistently recorded in all rats. Intrathecal tramadol dose-dependently reduced the amplitude and delayed the latency in both SSEPs and CMAP. Generally, the suppressive effects occurred immediately after injection and recovered over 2 h. Combined administration with 20 micro g of intrathecal naloxone did not attenuate the inhibition of spinal SSEPs. We conclude that intrathecal tramadol causes a dose-related suppressive effect on both sensory and motor neural conduction in the spinal cord. IMPLICATIONS: Spinal somatosensory-evoked potentials and evoked compound muscle action potential were used to evaluate the effects of intrathecal tramadol on sensory and motor neural conduction. Intrathecal tramadol dose-dependently reduced the amplitude and delayed the latency of both spinal somatosensory-evoked potentials and compound muscle action potential. These results indicate that tramadol exerts a dose-related central neural blockade. |
| tramadol |
c-Fos |
True Positive |
15102381 |
Kovelowski CJ, Raffa RB, Porreca F: Tramadol and its enantiomers differentially suppress c-fos-like immunoreactivity in rat brain and spinal cord following acute noxious stimulus. Eur J Pain. 1998;2(3):211-9. Tramadol hydrochloride, (1RS,2RS)-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an orally-active, centrally-acting analgesic with a putative dual mechanism of action, including an opioid and non-opioid component. The analgesic properties of tramadol and the possible co-existence of dual mechanisms has been postulated to be due to complementary and interactive pharmacologies of its enantiomers. We examined the ability of tramadol, its enantiomers, and morphine as reference to suppress c-fos-like immunoreactivity (c-fos-ir) in rat spinal cord and brain regions following a noxious stimulus (i.p. administration of 3.5% acetic acid). c-fos-ir was measured by immunocytochemistry and the stained cells in each region were counted 2 h after the acetic-acid injection (2:25 h after tramadol or morphine). Equi-analgesic doses of s.c. morphine (10 mg/kg) or tramadol (30 mg/kg) significantly suppressed c-fos-ir in all areas examined, except dorsal central gray of the spinal cord. The enantiomers of tramadol had distinctive patterns of suppression, neither one suppressed c-fos-ir in all of the regions, and hence neither one alone accounted for the suppression produced by the racemate. These findings support differential and complementary effects of tramadol enantiomers in sub-populations of spinal and supraspinal nociceptive neurons, consistent with the proposed antinociceptive interaction between the enantiomers. |
| tramadol |
c-Fos |
True Positive |
8925281 |
Traub RJ, Stitt S, Gebhart GF: Attenuation of c-Fos expression in the rat lumbosacral spinal cord by morphine or tramadol following noxious colorectal distention. Brain Res. 1995 Dec 1;701(1-2):175-82. We have previously reported that repetitive, noxious colorectal distention (CRD) induces c-Fos in the lumbosacral spinal cord. This study examined the effects of the analgesics morphine and tramadol on c-Fos expression resulting from noxious CRD in the rat. Pre-treatment (30 min or 1 min, i.v.) with morphine (1.25 mg/kg-5.0 mg/kg) or tramadol (1 mg/kg-20 mg/kg) dose-dependently attenuated c-Fos expression to CRD in all areas of the L6-S1 spinal gray matter. The highest dose of morphine was equipotent to the highest dose of tramadol. Repetitive dosing (1/4 of the greatest dose every 30 min) was as effective as a single bolus dose for both drugs. The visceromotor response to CRD was dose-dependently attenuated by tramadol and was reversed by naloxone. However, the dose of tramadol that eliminated the visceromotor response (7% of control) reduced the c-Fos expression to 47% of control. These results demonstrate that these two analgesics attenuate immediate-early gene expression and the visceromotor response to a noxious visceral stimulus and suggest that complete attenuation of c-Fos expression is not necessary for these compounds to produce analgesia to a noxious visceral stimulus. |
| tramadol |
CYP2D6 |
True Positive |
17361124 |
Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F: Concentrations of Tramadol and O-desmethyltramadol Enantiomers in Different CYP2D6 Genotypes. Clin Pharmacol Ther. 2007 Jul;82(1):41-7. Epub 2007 Mar 14. The influence of CYP2D6 genotype and CYP2D6 inhibitors on enantiomeric plasma levels of tramadol and O-desmethyltramadol as well as response to tramadol was investigated. One hundred and seventy-four patients received one hundred intravenous tramadol 3 mg/kg for postoperative analgesia. Blood samples drawn 30, 90, and 180 min after administration were analyzed for plasma concentrations of the enantiomers (+)-, (-) tramadol and (+)-, (-) O-desmethyltramadol by liquid chromatography-tandem mass spectrometry. Different CYP2D6 genotypes displaying zero (poor metabolizer (PM)), one (heterozygous individual (HZ)/intermediate metabolizer (IM)), two extensive metabolizer (EM), and three (ultra rapid metabolizer (UM)) active genes were compared. Concentrations of O-desmethyltramadol differed in the four genotype groups. Median (1/3 quartile) area under the concentration-time curves for (+) O-desmethyltramadol were 0 (0/11.4), 38.6 (15.9/75.3), 66.5 (17.1/118.4), and 149.7 (35.4/235.4) ng.h/ml for PMs, HZ/IMs, EMs, and UMs (P <0.001). Comedication with CYP2D6 inhibitors decreased (+) O-desmethyltramadol concentrations (P <0.01). In PMs, non-response rates to tramadol treatment increased fourfold compared with the other genotypes (P <0.001). In conclusion, CYP2D6 genotype determined concentrations of O-desmethyltramadol enantiomers and influenced efficacy of tramadol treatment.Clinical Pharmacology & Therapeutics (2007) 82, 41-47. doi:10.1038/sj.clpt.6100152; published online 14 March 2007. |
| tramadol |
CYP2D6 |
True Positive |
17175164 |
Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA: Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30. Epub 2006 Nov 23. OBJECTIVE: Our objective was to evaluate the effect of CYP2D6 phenotype in the enantioselective metabolism of tramadol in Spanish healthy human volunteers. METHODS: A single oral 100mg dose of racemic tramadol was administered to five subjects who were poor metabolizers (PMs) and 19 subjects who were extensive metabolizers (EMs), whose phenotypes were determined by the use of the racemic tramadol metabolic rate. The pharmacokinetic parameters were estimated from plasma concentrations of the enantiomers of tramadol and their main phase I metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol (M2). Epinephrine plasma concentrations were also determinated. RESULTS: The plasma concentrations of both tramadol enantiomers were consistently higher in PMs than in EMs of CYP2D6, with 1.98- and 1.74-fold differences in the mean area under the plasma concentration-time curves (AUC), respectively. The values for oral clearance of (+)- and (--)-tramadol were 1.91- and 1.71-fold greater in PMs, which were related to differences in both O-desmethylation and N-desmethylation in the two CYP2D6 metabolizer phenotypes. The mean AUC values of (+)-M1 and (--)-M1 were 4.33- and 0.89-fold greater in EMs, and it was related to similar differences in the formation rate constant. On the other hand, the differences were 7.40- and 8.69-fold greater in PMs for M2 enantiomers due to the involvement of CYP2D6 in their subsequent biotransformation. The time course of epinephrine systemic concentrations was completely different between both groups of metabolizers. In EMs plasma concentrations of epinephrine increased after tramadol administration whereas in PMs no effect was observed. CONCLUSIONS: The polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol enantiomers. The N-desmethylation pathway was indirectly affected by CYP2D6 phenotypic differences. Epinephrine showed a good correlation with the pharmacokinetics of the opioid component of tramadol, (+)-M1 and was found to be useful for its pharmacodynamic profiling. |
| tramadol |
CYP2D6 |
True Positive |
16961158 |
Allegaert K, Van den Anker JN, Debeer A, Cossey V, Verbesselt R, Tibboel D, Devlieger H, de Hoon J: Maturational changes in the in vivo activity of CYP3A4 in the first months of life. Int J Clin Pharmacol Ther. 2006 Jul;44(7):303-8. OBJECTIVE: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. METHODS: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. RESULTS: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. CONCLUSIONS: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed. |
| tramadol |
CYP2D6 |
True Positive |
16763825 |
Pedersen RS, Damkier P, Brosen K: Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Pharmacol. 2006 Jul;62(7):513-21. Epub 2006 Jun 9. OBJECTIVE: To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). METHODS: Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/-)-tramadol and (+/-)-M1 were determined for 48 h after administration. RESULTS: In all three phases, there were significant differences between EMs and PMs in AUC and t (1/2) of (+)-tramadol (P < or =0.0015), (-)-tramadol (P < or =0.0062), (+)-M1 (P < or =0.0198) and (-)-M1 (P < or =0.0370), and significant differences in C (max) of (+)-M1 (P <0.0001) and (-)-M1 (P < or =0.0010). In Phase A and C, significant differences in t (max) were seen for (+)-M1 (P < or =0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P <0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases. CONCLUSION: The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs. |
| tramadol |
CYP2D6 |
True Positive |
16631290 |
Susce MT, Murray-Carmichael E, de Leon J: Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Sep 30;30(7):1356-8. Epub 2006 Apr 24. Codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. Codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics, including tramadol, dihydrocodeine, oxycodone and hydrocodone, although they have been less systematically studied. It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics. |
| tramadol |
CYP2D6 |
True Positive |
16368820 |
Enggaard TP, Poulsen L, Arendt-Nielsen L, Brosen K, Ossig J, Sindrup SH: The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg. 2006 Jan;102(1):146-50. Tramadol analgesia results from a monoaminergic effect by tramadol itself and an opioid effect of its metabolite (+)-M1 formed by O-demethylation of tramadol by CYP2D6. In this study we sought to determine the impact of (+)-M1 on the analgesic effect of tramadol evaluated by experimental pain models. The effect of an IV injection of 100 mg tramadol on experimental pain was studied 15-90 min after dosing in volunteers, 10 extensive metabolizers with CYP2D6 and 10 poor metabolizers without CYP2D6 in 2 placebo-controlled trials. The pain tests included detection and tolerance threshold to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation (temporal summation), and the cold pressor test. In extensive metabolizers, tramadol reduced discomfort experienced during the cold pressor test (P = 0.002). In poor metabolizers, the pain tolerance thresholds to sural nerve stimulation were increased (P = 0.04). (+)-M1 could be detected in the serum samples from all extensive metabolizers except one, but (+)-M1 was below the limit of determination in all poor metabolizers. The opioid effect of (+)-M1 appears to contribute to the analgesic effect of tramadol, but the monoaminergic effect of tramadol itself seems to create an analgesic effect. |
| tramadol |
CYP2D6 |
True Positive |
16189332 |
Samer CF, Piguet V, Dayer P, Desmeules JA: [Genetic polymorphism and drug interactions: their importance in the treatment of pain]. Can J Anaesth. 2005 Oct;52(8):806-21. OBJECTIVES: To evaluate the impact of certain genetic polymorphisms on variable responses to analgesics SOURCES: Systematic review, by means of a structured computerized search in the Medline database (1966-2004). KEY WORDS: pharmacogenetics, polymorphism, cytochrome P450 (CYP), glycoprotein P (P-gp), pain, antalgics, opiates, morphine, codeine, tramadol, non-steroidal anti-inflammatory drugs (NSAID). Articles in English and French were selected. References in relevant articles were also retrieved. MAIN FINDINGS: Most analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as "weak" (codeine, tramadol), anti-depressants and dextromethorphan are metabolized by CYP2D6 and some "potent" opioids (buprenorphine, methadone or fentanyl) by CYP3A4/5. After the usual doses have been administered, drug toxicity or, on the contrary, therapeutic ineffectiveness may occur, depending on polymorphism and the substance. Drug interactions mimicking genetic defects because of the existence of CYP inhibitors and inducers, also contribute to the variable response to analgesics.Some opioids are substrates of P-gp, a transmembrane transporter also subject to genetic polymorphism. However, P-gp could only play a minor modulating role in man on the central effects of morphine, methadone and fentanyl. CONCLUSION: In the near future, pharmacogenetics should enable us to optimize therapeutics by individualizing our approach to analgesic drugs and making numerous analgesics safer and more effective. The clinical usefulness of these individualized approaches will have to be demonstrated by appropriate pharmacoeconomic studies and analyses. |
| tramadol |
CYP2D6 |
True Positive |
15951326 |
Allegaert K, Anderson BJ, Verbesselt R, Debeer A, de Hoon J, Devlieger H, Van Den Anker JN, Tibboel D: Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity. Br J Anaesth. 2005 Aug;95(2):231-9. Epub 2005 Jun 10. BACKGROUND: Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available. METHODS: A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity. RESULTS: Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h (-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance. CONCLUSIONS: Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre (-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg (-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg (-1) h (-1) at 25 weeks PCA, 0.14 mg kg (-1) h (-1) at 30 weeks PCA, 0.17 mg kg (-1) h (-1) at 35 weeks PCA, 0.18 mg kg (-1) h (-1) at 40 weeks, 0.19 mg kg (-1) h (-1) at 50 weeks PCA to 1 yr, 0.18 mg kg (-1) h (-1) at 3 yr and 0.12 mg kg (-1) h (-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established. |
| tramadol |
CYP2D6 |
True Positive |
15197521 |
Hedenmalm K, Lindh JD, Sawe J, Rane A: Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene. Eur J Clin Pharmacol. 2004 Jul;60(5):369-72. Epub 2004 Jun 10. OBJECTIVE: This study aimed to investigate the importance of cytochrome P (450) enzymes for the reported interaction between tramadol and warfarin. MATERIALS AND METHODS: Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19. RESULTS: Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition. CONCLUSION: The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity. |
| tramadol |
CYP2D6 |
True Positive |
15042506 |
Brack A, Bottiger BW, Schafer M: [New insights in postoperative pain therapy] . Anasthesiol Intensivmed Notfallmed Schmerzther. 2004 Mar;39(3):157-64. In this review, novel clinical studies on postoperative pain therapy are summarized. Based on these studies, several conclusions can be drawn: i) following tonsillectomy, postoperative therapy with NSAIDs leads to a significant increase in the number of reoperations; thus NSAIDs should be used with caution; ii) COX-2 inhibitors in combination with intravenous opioids improve recovery and functional outcome after knee replacement surgery; iii) the combination therapy of different non-opioid analgesics has no proven clinical efficacy and should not be used routinely; iv) patients' age is not a determinant in postoperative opioid titration after surgery; in contrast, it does predict opioid consumption during the first postoperative day; v) morphine and piritramide have identical analgesic efficacy and induce nausea and vomiting with the incidence; opioid selection can, thus, be based on economic considerations and vi) if tramadol is ineffective in postoperative pain therapy, this might be caused by an allelic variant of one of the cytochrome P450 enzymes (CYP2D6); these patients should be treated with a different opioid. |
| tramadol |
5-HT3 |
True Positive |
16427041 |
Barann M, Urban B, Stamer U, Dorner Z, Bonisch H, Bruss M: Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis. J Pharmacol Exp Ther. 1992 Dec;263(3):1015-22. ([3H] 5-HT)-uptake and patch-clamp techniques were used to study the actions of (+) and (-) tramadol and the active metabolites of tramadol, (+) and (-) O-demethyl-tramadol on the human serotonin (5-HT) transporter and the human 5-HT3A receptor, stably expressed in HEK-293 cells. The (+) and (-) enantiomers of tramadol suppressed the human 5-HT transporter concentration-dependently (IC50=1.0 and 0.8 microM, respectively), resulting in 97% and 87% transport inhibition at their respective initial plasma concentrations (9.5 microM). The (+) and (-) enantiomers of the active tramadol metabolite were less potent than tramadol in inhibiting the human 5-HT transporter (IC50=15 and 44 microM, respectively), resulting in 19.2% and 4.8% transport inhibition at their highest plasma concentrations (2.5 microM). In contrast to their potent suppression of the 5-HT transporter, both, (+) and (-) tramadol inhibited 5-HT (30 microM)-induced currents only at substantially higher concentrations (IC50=199 and 251 microM, respectively), resulting in only 6% and 4% inhibition at the initial maximum plasma concentration. A similar low potent inhibition of human 5-HT (3A) receptors was found for (+) and (-) O-demethyl-tramadol (IC50=158 and 63 microM, respectively). In conclusion, at clinical plasma concentrations tramadol potently suppresses the human 5-HT transporter, whereas it has only a slight effect on the human 5-HT3A receptor. The results are compatible with a possible mechanism for tramadol-induced early emesis involving the serotonergic system. |
| tramadol |
5-HT3 |
True Positive |
12032025 |
Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A: Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT (3) spinal receptor involvement in acute pain in humans. Anesth Analg. 2002 Jun;94(6):1553-7 To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT (3)), we evaluated the effects of a coadministration of ondansetron, a 5-HT (3) selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg. mL (-1). h (-1)) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never > 4, according to a 0-10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002). Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT (3) receptors. IMPLICATIONS: Serotonin is an important neurotransmitter of the descending pathways that down-modulate spinal nociception. In postoperative pain, ondansetron, a selective 5-HT (3) receptor antagonist, increased the analgesic dose of tramadol. We suggest that, when antagonized for antiemetic purpose, 5-HT (3) receptors foster nociception, because of their site-dependent action. |
| tramadol |
IL-10 |
True Positive |
16171665 |
Wang G, Weng Y, Ishiguro Y, Sakamoto H, Morita S: The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J Clin Anesth. 2005 Sep;17(6):444-50. STUDY OBJECTIVE: To investigate the effect of tramadol on the production of serum interleukin (IL) 6, IL-10, and IL-2 and soluble (s) IL-2 receptor (R), thereby evaluating its effects on the proinflammatory and anti-inflammatory responses and immune function in cancer patients undergoing conventional pulmonary lobectomy. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II adult patients scheduled for conventional pulmonary lobectomy. INTERVENTIONS: Patients were randomly divided into 2 groups (n = 20 in each group). Both groups received general anesthesia with enflurane combined with epidural blockade. At 5 minutes before skin incision, patients were given either tramadol 1.5 mg/kg intravenously (IV), followed by a continuous infusion of 0.5 mg/kg per hour until the end of surgery (group I), or IV normal saline (group II). MEASUREMENTS AND MAIN RESULTS: Venous blood samples for the measurement of serum cytokine concentrations were taken before anesthesia and at set intervals until 24 hours after operation. Serum levels of IL-6 and IL-10 in both groups were increased significantly during and after operation compared with baseline levels (P < .05). No statistical differences between groups in terms of IL-6 and IL-10 were observed. Levels of IL-2 were elevated significantly at 4 hours after operation in group I as compared with baseline levels (P < .001), whereas they remained low at 4 and 24 hours after operation in group II (P < .01). There were significant increases in levels of sIL-2R at 4 and 24 hours after operation in group II as compared with baseline levels (P < .05) and at 24 hours after operation in group I (P < .01). Levels of IL-2 were higher at 4 and 24 hours after operation in group I than in group II (P < .01). Levels of sIL-2R were lower at 4 hours after operation in group I than in group II (P < .01). CONCLUSIONS: IV infusion of tramadol does not seem to alter IL-6/IL-10 cytokine response to pulmonary lobectomy. As tramadol was associated with increased IL-2 and delayed enhancement of sIL-2R in our study, it may attenuate to some extent an impaired immune response in pulmonary lobectomy. |
| tramadol |
CYP3A4 |
True Positive |
16961158 |
Allegaert K, Van den Anker JN, Debeer A, Cossey V, Verbesselt R, Tibboel D, Devlieger H, de Hoon J: Maturational changes in the in vivo activity of CYP3A4 in the first months of life. Int J Clin Pharmacol Ther. 2006 Jul;44(7):303-8. OBJECTIVE: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. METHODS: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. RESULTS: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. CONCLUSIONS: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed. |
| tramadol |
CYP3A4 |
True Positive |
16189332 |
Samer CF, Piguet V, Dayer P, Desmeules JA: [Genetic polymorphism and drug interactions: their importance in the treatment of pain]. Can J Anaesth. 2005 Oct;52(8):806-21. OBJECTIVES: To evaluate the impact of certain genetic polymorphisms on variable responses to analgesics SOURCES: Systematic review, by means of a structured computerized search in the Medline database (1966-2004). KEY WORDS: pharmacogenetics, polymorphism, cytochrome P450 (CYP), glycoprotein P (P-gp), pain, antalgics, opiates, morphine, codeine, tramadol, non-steroidal anti-inflammatory drugs (NSAID). Articles in English and French were selected. References in relevant articles were also retrieved. MAIN FINDINGS: Most analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as "weak" (codeine, tramadol), anti-depressants and dextromethorphan are metabolized by CYP2D6 and some "potent" opioids (buprenorphine, methadone or fentanyl) by CYP3A4/5. After the usual doses have been administered, drug toxicity or, on the contrary, therapeutic ineffectiveness may occur, depending on polymorphism and the substance. Drug interactions mimicking genetic defects because of the existence of CYP inhibitors and inducers, also contribute to the variable response to analgesics.Some opioids are substrates of P-gp, a transmembrane transporter also subject to genetic polymorphism. However, P-gp could only play a minor modulating role in man on the central effects of morphine, methadone and fentanyl. CONCLUSION: In the near future, pharmacogenetics should enable us to optimize therapeutics by individualizing our approach to analgesic drugs and making numerous analgesics safer and more effective. The clinical usefulness of these individualized approaches will have to be demonstrated by appropriate pharmacoeconomic studies and analyses. |
| tramadol |
CYP3A4 |
True Positive |
11454734 |
Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG: Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos. 2001 Aug;29(8):1146-55. The metabolism of cis-tramadol has been studied in human liver microsomes and in cDNA-expressed human cytochrome P-450 (CYP) isoforms. Human liver microsomes catalyzed the NADPH-dependent metabolism of tramadol to the two primary tramadol metabolites, namely, O-desmethyl-tramadol (metabolite M1) and N-desmethyl-tramadol (metabolite M2). In addition, tramadol was also metabolized to two minor secondary metabolites (each comprising < or =3.0% of total tramadol metabolism), namely, N,N-didesmethyl-tramadol (metabolite M3) and N,O-didesmethyl-tramadol (metabolite M5). Kinetic analysis revealed that multiple CYP enzymes were involved in the metabolism of tramadol to both M1 and M2. For the high-affinity enzymes involved in M1 and M2 formation, K (m) values were 116 and 1021 microM, respectively. Subsequent reaction phenotyping studies were performed with a tramadol substrate concentration of 250 microM. In studies with characterized human liver microsomal preparations, good correlations were observed between tramadol metabolism to M1 and M2 and enzymatic markers of CYP2D6 and CYP2B6, respectively. Tramadol was metabolized to M1 by cDNA-expressed CYP2D6 and to M2 by CYP2B6 and CYP3A4. Tramadol metabolism in human liver microsomes to M1 and M2 was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. In summary, this study demonstrates that cis-tramadol can be metabolized to tramadol metabolites M1, M2, M3, and M5 in human liver microsomal preparations. By kinetic analysis and the results of the reaction phenotyping studies, tramadol metabolism in human liver is catalyzed by multiple CYP isoforms. Hepatic CYP2D6 appears to be primarily responsible for M1 formation, whereas M2 formation is catalyzed by CYP2B6 and CYP3A4. |
| tramadol |
interleukin |
False Positive |
16171665 |
Wang G, Weng Y, Ishiguro Y, Sakamoto H, Morita S: The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J Clin Anesth. 2005 Sep;17(6):444-50. STUDY OBJECTIVE: To investigate the effect of tramadol on the production of serum interleukin (IL) 6, IL-10, and IL-2 and soluble (s) IL-2 receptor (R), thereby evaluating its effects on the proinflammatory and anti-inflammatory responses and immune function in cancer patients undergoing conventional pulmonary lobectomy. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II adult patients scheduled for conventional pulmonary lobectomy. INTERVENTIONS: Patients were randomly divided into 2 groups (n = 20 in each group). Both groups received general anesthesia with enflurane combined with epidural blockade. At 5 minutes before skin incision, patients were given either tramadol 1.5 mg/kg intravenously (IV), followed by a continuous infusion of 0.5 mg/kg per hour until the end of surgery (group I), or IV normal saline (group II). MEASUREMENTS AND MAIN RESULTS: Venous blood samples for the measurement of serum cytokine concentrations were taken before anesthesia and at set intervals until 24 hours after operation. Serum levels of IL-6 and IL-10 in both groups were increased significantly during and after operation compared with baseline levels (P < .05). No statistical differences between groups in terms of IL-6 and IL-10 were observed. Levels of IL-2 were elevated significantly at 4 hours after operation in group I as compared with baseline levels (P < .001), whereas they remained low at 4 and 24 hours after operation in group II (P < .01). There were significant increases in levels of sIL-2R at 4 and 24 hours after operation in group II as compared with baseline levels (P < .05) and at 24 hours after operation in group I (P < .01). Levels of IL-2 were higher at 4 and 24 hours after operation in group I than in group II (P < .01). Levels of sIL-2R were lower at 4 hours after operation in group I than in group II (P < .01). CONCLUSIONS: IV infusion of tramadol does not seem to alter IL-6/IL-10 cytokine response to pulmonary lobectomy. As tramadol was associated with increased IL-2 and delayed enhancement of sIL-2R in our study, it may attenuate to some extent an impaired immune response in pulmonary lobectomy. |
| tramadol |
opioid-receptor |
True Positive |
17572099 |
Loram LC, Mitchell D, Skosana M, Fick LG: Tramadol is more effective than morphine and amitriptyline against ischaemic pain but not thermal pain in rats. Pharmacol Res. 2007 Jul;56(1):80-5. Epub 2007 May 1. The aim of this study was to compare the analgesic efficacies of tramadol, which acts on opioid receptors and inhibits monoamine reuptake, to amitriptyline, a monoamine reuptake inhibitor as well as to morphine, an opioid receptor agonist. We compared the motor function impairment and response latencies to noxious thermal and noxious ischaemic challenges after tramadol administration to those after morphine and after amitriptyline administration. We injected Sprague-Dawley rats (i.p.) with either tramadol (1, 5, 15 and 25mgkg (-1)), morphine (0.01, 0.1, 1 and 5mgkg (-1)) or amitriptyline (1, 3 and 10mgkg (-1)) and a control injection of saline (100mul). We measured the tail flick latency to a noxious thermal challenge after tail immersion in a 49 degrees C water bath and response latency to noxious ischaemia, induced by a tourniquet inflated at the base of the tail, was recorded as ischaemic escape latency. In a separate group of rats, we assessed motor function by placing the rats on a rotarod, rotating at 25rpm, for a maximum of 30min after drug administration. We recorded the time to the rat's third fall from the rotarod. Tramadol (15mgkg (-1)) produced a 107% increase in response latency from pre-injection value as did 25mgkg (-1) tramadol (79%), 1mgkg (-1) morphine (85%), 5mgkg (-1) morphine (138%) and 10mgkg (-1) amitriptyline (46%) against a noxious thermal challenge. The escape latency against noxious ischaemia after morphine and amitriptyline administration did not change, despite an increase in dose, while increasing doses of tramadol (1-25mgkg (-1)) provided increasing analgesia against noxious ischaemia. Significant impairment to motor function occurred after morphine (5mgkg (-1)), tramadol (15mgkg (-1)) and amitriptyline (10mgkg (-1)) administration, with only 11, 50 and 38% of animals, respectively, completing the rotarod trial, compared to 100% completion after saline administration. As previously demonstrated, morphine was more potent than tramadol for the relief of thermal pain but tramadol may be a more beneficial drug for relieving severe ischaemic pain. |
| tramadol |
opioid-receptor |
True Positive |
10683712 |
Freye E, Latasch L: Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex. Arzneimittelforschung. 2000 Jan;50(1):24-30. As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced. |
| tramadol |
opioid-receptor |
True Positive |
1519677 |
Vickers MD, O'Flaherty D, Szekely SM, Read M, Yoshizumi J: Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992 Apr;47(4):291-6. Two independent clinical trials were conducted simultaneously. In one, tramadol and pethidine were compared in 30 patients by patient-controlled analgesia during the first 24 h following abdominal surgery. The mean 24 h consumption of tramadol and pethidine was 642 mg and 606 mg respectively, giving a potency estimate of tramadol relative to pethidine of 0.94 (95% confidence interval 0.72-1.17). In the second trial, the effect on respiration of three doses of tramadol (0.5, 1.0, and 2.0 mg.kg-1) was compared with that of morphine sulphate (0.143 mg.kg-1) by intravenous injection during stable halothane anaesthesia. At approximately 1.5 times the equipotent dose, as estimated from the first trial, tramadol transiently depressed the rate of respiration but had no effect on end-tidal carbon dioxide tension. Morphine caused apnoea or considerable depression of ventilation. The results suggest that mechanisms other than opioid receptor activity play a significant role in the analgesia produced by tramadol. |
| tramadol |
FMLP |
False Positive |
10226767 |
Bianchi M, Rossoni G, Sacerdote P, Panerai AE: Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol. 1999;13(2):220-5. We examined the ability of the analgesic drug tramadol to affect the development of inflammation in rats. The acute administration of tramadol significantly reduced the edema and the hyperalgesia induced by yeast injection in the paw. Moreover, in the subcutaneous carrageenin-induced inflammation, tramadol reduced the amount of the exudate, as well as the prostaglandin (PG) E2-like bio- and immuno-activity in the exudate; on the contrary, leukotriene (LT) B4 concentrations in the exudate were not changed. However, tramadol did not affect the ability of macrophages to migrate towards the chemotactic peptide N-formyl-L-methionil-L-leucyl-L-phenylalanine (FMLP). Our results suggest that tramadol is able to inhibit the development of different types of inflammation in the rat without affecting immune mechanisms, and contribute to explain the efficacy of this drug in the treatment of inflammatory pain. |
| tramadol |
prolactin |
True Positive |
6297329 |
Seitz W, Kirchner E, Schaps D, Wagner T, Hesch RD: [Endocrine reaction pattern in the course of a one-phase tramadol-N2O combination anesthesia]. Anasth Intensivther Notfallmed. 1982 Dec;17(6):325-31. The effects of Tramadol-N2O-anaesthesia on the per- and postoperative change in blood concentrations of cortisol, prolactin, thyroxine, triiodothyronine, cyclic AMP, glucagon, antidiuretic hormone, PTH-peptide (44-68), glucose, lactate, pyruvate and free fatty acids (FFA) were investigated in connection with elective orthopaedic surgery. Anaesthesia in man with Tramadol and nitrous oxide were found to be associated with a significant elevation of plasma cortisol and plasma prolactin in man. However, cortisol secretion during anaesthesia is associated with an inhibition in T4-T3 conversion. No significant alterations in plasma glucagon concentrations were observed. Generally, surgical trauma induced a significant increase in plasma cyclic AMP with intraoperative levels between 26.4 and 34.3 pmol/ml. At the end of surgery a significant fall in plasma PTH-peptide (44-68) occurred. There was also a significant change in plasma ADH levels following induction of anaesthesia. During surgery we found plasma ADH levels up to 56 pg/ml. In addition stress and surgical trauma increased blood glucose and FFA while plasma pyruvate and plasma lactate nearly remained unchanged. The data would suggest that the non-specific stress response attributed to anaesthesia may in fact be reflecting a response to relatively light anaesthesia. |
| tramadol |
IL-6 |
True Positive |
16171665 |
Wang G, Weng Y, Ishiguro Y, Sakamoto H, Morita S: The effect of tramadol on serum cytokine response in patients undergoing pulmonary lobectomy. J Clin Anesth. 2005 Sep;17(6):444-50. STUDY OBJECTIVE: To investigate the effect of tramadol on the production of serum interleukin (IL) 6, IL-10, and IL-2 and soluble (s) IL-2 receptor (R), thereby evaluating its effects on the proinflammatory and anti-inflammatory responses and immune function in cancer patients undergoing conventional pulmonary lobectomy. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II adult patients scheduled for conventional pulmonary lobectomy. INTERVENTIONS: Patients were randomly divided into 2 groups (n = 20 in each group). Both groups received general anesthesia with enflurane combined with epidural blockade. At 5 minutes before skin incision, patients were given either tramadol 1.5 mg/kg intravenously (IV), followed by a continuous infusion of 0.5 mg/kg per hour until the end of surgery (group I), or IV normal saline (group II). MEASUREMENTS AND MAIN RESULTS: Venous blood samples for the measurement of serum cytokine concentrations were taken before anesthesia and at set intervals until 24 hours after operation. Serum levels of IL-6 and IL-10 in both groups were increased significantly during and after operation compared with baseline levels (P < .05). No statistical differences between groups in terms of IL-6 and IL-10 were observed. Levels of IL-2 were elevated significantly at 4 hours after operation in group I as compared with baseline levels (P < .001), whereas they remained low at 4 and 24 hours after operation in group II (P < .01). There were significant increases in levels of sIL-2R at 4 and 24 hours after operation in group II as compared with baseline levels (P < .05) and at 24 hours after operation in group I (P < .01). Levels of IL-2 were higher at 4 and 24 hours after operation in group I than in group II (P < .01). Levels of sIL-2R were lower at 4 hours after operation in group I than in group II (P < .01). CONCLUSIONS: IV infusion of tramadol does not seem to alter IL-6/IL-10 cytokine response to pulmonary lobectomy. As tramadol was associated with increased IL-2 and delayed enhancement of sIL-2R in our study, it may attenuate to some extent an impaired immune response in pulmonary lobectomy. |
| tramadol |
mu-1 |
False Positive |
9235725 |
De Conno F, Polastri D: [Treatment of pain in oncology] . Tumori. 1997;83(2 Suppl):S20-4. Basic guidelines for cancer pain treatment can be found in many different handbooks published in the last years. Particularly those of the World Health Organisation published in 1986 and revised in 1996, furnish useful indication for cancer pain treatment. The authors therefore focused on resuming the most recent development in this field. In the research regarding alternative routes of administration of opioids in alternative to the oral route, the rectal administration of morphine and methadone and the transdermal route for fentanyl have proved to be efficacious. The subcutaneous route (for morphine) as well as the intravenous, peridural and subaracnoid routes, being known for some time are not taken in consideration in this paper. Various studies suggest that alternative routes are necessary in 53-70% of patients in their last days or months of live. The most frequent causes for the need to stop oral administration are dysphagia, nausea, and uncontrollable vomiting, bowel obstruction, malabsorption, cognitive failure, coma, and pain syndromes requiring anaesthetics which need be administered via the spinal route. Among the drugs, tramadol seems to be effective in the control of moderate pain. Tramadol is a centrally acting analgesic drug; it has an agonist effect on mu 1 receptors of opioids and acts also by inhibiting the re-uptake of noradrenaline and serotonine which activates descending monoaminergic inhibitory pathways. Recent clinical studies revealed that pamidronate has an analgesic effect in pain due to bone metastasis. Pamidronate is part of the biphosphonates, which are active on bone metabolism and are usually being used for the treatment of hypercalcaemia in cancer. The authors also describe briefly the indication of ketamin in association with morphine for the treatment of neuropathic pain. |
| tramadol |
5-HT-2C |
True Positive |
16679816 |
Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A: The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes. Pharmacology. 2006;77(2):93-9. Epub 2006 May 5. PURPOSE: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT (2C) R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT (2C) R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT (2C) R expressed in Xenopus oocytes. METHODS: We examined the effect of O-desmethyl tramadol on 5-HT (2C) R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3) H] 5-HT by 5-HT (2C) R. RESULTS: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca (2+)-activated Cl (-) currents in oocytes that expressed 5-HT (2C) R. The inhibitory effect of O-desmethyl tramadol on 5-HT (2C) R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3) H] 5-HT by 5-HT (2C) R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3) H] 5-HT by 5-HT (2C) R without changing maximum binding, which indicated competitive inhibition. CONCLUSION: These results suggest that O-desmethyl tramadol inhibits 5-HT (2C) R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol. |
| tramadol |
5-HT-2C |
True Positive |
15105221 |
Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y: The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg. 2004 May;98(5):1401-6 Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT (2C) R) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca (2+)-activated Cl (-) currents mediated by 5-HT (2C) R expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl (-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT (2C) R-mediated events. We also studied the effects of tramadol on [(3) H] 5-HT binding to 5-HT (2C) R expressed in Xenopus oocytes, and found that it inhibited the specific binding of [(3) H] 5-HT to 5-HT (2C) R. Scatchard analysis of [(3) H] 5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT (2C) R function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT (2C) R, rather than via activation of the PKC pathway. IMPLICATIONS: We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT (2C) R) expressed in Xenopus oocytes. Tramadol inhibited 5-HT (2C) R function and the specific binding of [(3) H] 5-HT to 5-HT (2C) R in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT (2C) R might involve the competitive displacement of 5-HT binding to the 5-HT (2C) R. |
| tramadol |
cyclooxygenase-2 |
True Positive |
17622776 |
Kamerman P, Koller A, Loram L: Postoperative Administration of the Analgesic Tramadol, but Not the Selective Cyclooxygenase-2 Inhibitor Parecoxib, Abolishes Postoperative Hyperalgesia in a New Model of Postoperative Pain in Rats. Pharmacology. 2007 Jul 6;80(4):244-248. Background/Aims: Using a new animal model of postoperative pain we recently developed, we investigated whether the selective cyclooxygenase-2 (COX-2) inhibitor pare-coxib sodium, and the analgesic tramadol hydrochloride, attenuated mechanical primary hyperalgesia induced by minor surgery on the rat tail. Methods: For surgery, rats were anesthetized with isoflurane, a 20-mm-long incision was made through the skin and fascia of their tails, and the wound was sutured. Immediately after surgery, rats were injected intraperitoneally with parecoxib sodium (10 or 20 mg.kg (-1)), tramadol hydrochloride (10 mg.kg (-1)), or sterile saline (0.1 ml.kg (-1)). Hyperalgesia was assessed by measuring rats' response latencies to a blunt noxious mechanical stimulus (4 N) applied to their tails. Nociceptive testing was performed before surgery and 90 min after surgery. Results: Hyperalgesia was present in all saline-injected animals within 90 min of surgery. This hyperalgesia was not attenuated by postoperative injection of parecoxib. However, administration of tramadol completely prevented the development of postoperative hyperalgesia. Conclusion: We have shown that the hyperalgesia in our model of postoperative pain is responsive to treatment with the analgesic tramadol, but it is not responsive to the selective COX-2 inhibitor parecoxib at the doses we used. Copyright (c) 2007 S. Karger AG, Basel. |
| tramadol |
cyclooxygenase-2 |
True Positive |
15060515 |
Punwani NG: Tramadol pharmacokinetics and its possible interactions with cyclooxygenase 2-selective nonsteroidal anti-inflammatory drugs. Clin Pharmacol Ther. 2004 Apr;75(4):363-5. |
| tramadol |
cyclooxygenase-2 |
True Positive |
14705234 |
Emkey R, Rosenthal N, Wu SC, Jordan D, Kamin M: Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Pathol. 2000 Sep;157(3):737-45. OBJECTIVE: To evaluate the efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) as add-on therapy for subjects with osteoarthritis (OA) pain inadequately controlled by COX-2 nonsteroidal antiinflammatory drugs (NSAID). METHODS: This 91-day, multicenter, randomized, double-blind, placebo-controlled trial enrolled subjects with symptomatic OA for >/= 1 year who experienced at least moderate pain [visual analog scale (VAS) score >/= 50/100 mm] despite treatment with stable doses of celecoxib (>/= 200 mg/day) or rofecoxib (>/= 25 mg/day). Tramadol/APAP or matching placebo was titrated to 4 tablets/day on Day 10 and thereafter as needed up to 8 tablets/day. The primary efficacy measure was final VAS score; secondary measures included final pain relief rating scores, subject/investigator overall medication assessments, rate and time to discontinuation due to lack of efficacy, and selected quality-of-life/physical functioning scores. RESULTS: Of 307 subjects randomized, 306 taking celecoxib (56.5%) or rofecoxib (43.5%) were included in the intent-to-treat population (n = 153 tramadol/APAP, 153 placebo). Mean final VAS scores for tramadol/APAP plus COX-2 NSAID were significantly lower than placebo plus COX-2 NSAID (41.5 vs 48.3; p = 0.025) and mean final pain relief rating scores were significantly higher (p = 0.002). Subjects taking tramadol/APAP showed significant improvements compared with placebo in subject/investigator medication assessments, as well as in the WOMAC Physical Function and the Medical Outcome Study Short Form-36 Role-Physical measures. The most common treatment-related adverse events for tramadol/APAP were somnolence (6.5%), nausea (4.6%), and constipation (3.3%). Mean tramadol/APAP dose was 4.1 tablets (154 mg tramadol/ 1332 mg APAP). CONCLUSION: Tramadol 37.5 mg/APAP 325 mg combination tablets were effective and safe as add-on therapy with COX-2 NSAID for treatment of OA pain. |
| tramadol |
cyclooxygenase-2 |
True Positive |
11124014 |
Buccellati C, Sala A, Ballerio R, Bianchib M: Tramadol anti-inflammatory activity is not related to a direct inhibitory action on prostaglandin endoperoxide synthases. Eur J Pain. 2000;4(4):413-5. The analgesic drug tramadol has been shown to relieve pain in inflammatory conditions, to inhibit the development of experimental inflammation, and to reduce prostaglandin (PG) E (2) concentrations in the inflammatory exudate. In this study, we evaluated the putative activity of tramadol to suppress prostaglandin endoperoxide synthase-1 (PGHS-1), and prostaglandin endoperoxide synthase-2 (PGHS-2) activities in human whole blood in vitro. Platelet thromboxane (Tx) B (2) production and monocyte PGE (2) production in LPS- stimulated blood were measured in samples incubated with different concentrations (300 ng/ml, 3 microg/ml, 30 microg/ml) of tramadol or its enantiomers. Neither tramadol nor the enantiomers inhibited the formation of arachidonic acid metabolites. Our results indicate that the anti-inflammatory effect of tramadol demonstrated in some models is not related to a direct inhibitory effect on the formation of prostanoids. |
| tramadol |
cytochrome-P450 |
True Positive |
17570739 |
Gan SH, Ismail R, Wan Adnan WA, Zulmi W: Impact of CYP2D6 Genetic Polymorphism on Tramadol Pharmacokinetics and Pharmacodynamics. Mol Diagn Ther. 2007;11(3):171-81. BACKGROUND AND OBJECTIVE: Tramadol is metabolized by the highly polymorphic enzyme cytochrome P450 (CYP) 2D6. Patients with different CYP2D6 genotypes may respond differently to tramadol in terms of pain relief and adverse events. In this study, we compare the pharmacokinetics and effects of tramadol in Malaysian patients with different genotypes to establish the pharmacokinetic-pharmacodynamic relationship of tramadol. STUDY DESIGN AND SETTING: All patients received an intravenous dose of tramadol 100mg as their first postoperative analgesic. Blood was sampled at 0 minutes and subsequently at 15 and 30 minutes, 1, 2, 4, 8, 16, 20, and 24 hours for serum tramadol and analyzed by high-performance liquid chromatography (HPLC). Patients were genotyped for CYP2D6*1, *3, *4, *5, *9, *10, and *17 alleles and duplication of the gene by means of an allele-specific PCR. Pain was measured using the Visual Analog Scales, and adverse effects were recorded. RESULTS: About half of the patients had the wild-type allele (CYP2D6*1), with the 'Asian'CYP2D6*10 allele accounting for most of the rest (40%). None of the genotypes predicted poor metabolism. Twenty-seven percent of the patients were intermediate metabolizers (IM) and 2.9% were ultra-rapid (UM) metabolizers; the remaining 70% were extensive metabolizers (EM). The mean total clearance (CL) predicted by the model was lower (19 L/h) and the half-life longer (5.9 hours) than those reported in Western populations. This may due to the high frequency of the CYP2D6*10 allele amongst Malaysian patients. The UM and EM groups had 2.6- and 1.3-times faster CL, respectively, than the IM. CL was 16, 18, 23, and 42 L/h while mean half-lives were 7.1, 6.8, 5.6, and 3.8 hours among the IM, EM1, EM2, and UM groups, respectively. However, the analgesic effects of tramadol were not measured adequately among the postoperative patients to establish its full therapeutic effects. There were significant differences in the adverse-effect profiles amongst the various genotype groups, with the IM group experiencing more adverse effects than the EM, and the EM having more adverse effects than the UM. CONCLUSION: CYP2D6 activity may play an important role in determining the pharmacokinetics of tramadol and in predicting its adverse effects. If these results can be confirmed in a larger population, genotyping may be an important tool in determining the dose of tramadol. |
| tramadol |
cytochrome-P450 |
True Positive |
15592335 |
Tirkkonen T, Laine K: Drug interactions with the potential to prevent prodrug activation as a common source of irrational prescribing in hospital inpatients. Clin Pharmacol Ther. 2004 Dec;76(6):639-47. OBJECTIVE: Our objective was to investigate the frequency of potential drug-drug interactions between the prodrugs losartan, codeine, and tramadol and drugs known to inhibit their activation in hospitalized patients. METHODS: The frequency of coadministration between losartan and well-established cytochrome P450 (CYP) 2C9 inhibitors, as well as codeine and tramadol and CYP2D6 inhibitors, was studied by use of data from a university hospital medication database. The study population comprised all patients treated in internal medicine, pulmonary medicine, oncology, and neurology wards (105,533 treatment periods and 65,526 patients) between July 1, 1996, and June 30, 2002 (6 years). RESULTS: Every fifth patient receiving losartan, codeine, or tramadol was concomitantly taking another drug that has the potential to inhibit the activation of these drugs. During the 6-year time period, 1999 patients were exposed to a potential interaction. Interactions occurred more commonly in internal medicine wards (odds ratio, 2.3; 95% confidence interval, 2.1-2.5) and in women (odds ratio, 1.5; 95% confidence interval, 1.4-1.7). CONCLUSIONS: Coadministration of drugs that potentially result in inhibition of prodrug activation present a common and unrecognized source of irrational prescribing. |
| tramadol |
cytochrome-P450 |
True Positive |
15509185 |
Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids. |
| tramadol |
cytochrome-P450 |
True Positive |
15197521 |
Hedenmalm K, Lindh JD, Sawe J, Rane A: Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene. Eur J Clin Pharmacol. 2004 Jul;60(5):369-72. Epub 2004 Jun 10. OBJECTIVE: This study aimed to investigate the importance of cytochrome P (450) enzymes for the reported interaction between tramadol and warfarin. MATERIALS AND METHODS: Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19. RESULTS: Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition. CONCLUSION: The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity. |
| tramadol |
cytochrome-P450 |
True Positive |
15042506 |
Brack A, Bottiger BW, Schafer M: [New insights in postoperative pain therapy] . Anasthesiol Intensivmed Notfallmed Schmerzther. 2004 Mar;39(3):157-64. In this review, novel clinical studies on postoperative pain therapy are summarized. Based on these studies, several conclusions can be drawn: i) following tonsillectomy, postoperative therapy with NSAIDs leads to a significant increase in the number of reoperations; thus NSAIDs should be used with caution; ii) COX-2 inhibitors in combination with intravenous opioids improve recovery and functional outcome after knee replacement surgery; iii) the combination therapy of different non-opioid analgesics has no proven clinical efficacy and should not be used routinely; iv) patients' age is not a determinant in postoperative opioid titration after surgery; in contrast, it does predict opioid consumption during the first postoperative day; v) morphine and piritramide have identical analgesic efficacy and induce nausea and vomiting with the incidence; opioid selection can, thus, be based on economic considerations and vi) if tramadol is ineffective in postoperative pain therapy, this might be caused by an allelic variant of one of the cytochrome P450 enzymes (CYP2D6); these patients should be treated with a different opioid. |
| tramadol |
cytochrome-P450 |
True Positive |
12842359 |
Clarot F, Goulle JP, Vaz E, Proust B: Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? . Forensic Sci Int. 2003 Jun 24;134(1):57-61. Tramadol is a centrally acting analgesic agent used in the treatment of mild to moderate pain. It has a low affinity to opioid receptors and inhibits the reuptake of norepinephrin and serotonin producing an analgesic action by blocking nociceptive impulses in the spine. Although 21 drug-combined fatalities including tramadol have been reported, only two fatal overdoses in adults with tramadol alone have been reported to date. We report four additional lethal intoxications, assess the toxicity of tramadol, the detection method and the possible interaction with other central nervous system (CNS) depressants, particularly benzodiazepines. Similarities between tramadol and buprenorphine are discussed, and a possible cytochrome P450-based interaction between tramadol and benzodiazepine is considered. To our knowledge, this relationship has never been reported in the literature. |
| tramadol |
norepinephrine-transporter |
True Positive |
11916794 |
Sagata K, Minami K, Yanagihara N, Shiraishi M, Toyohira Y, Ueno S, Shigematsu A: Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg. 2002 Apr;94(4):901-6 Tramadol is a widely used analgesic, but its mode of action is not well understood. To study the effects of tramadol on norepinephrine transporter (NET) function, we assayed the effect of tramadol on [3H]-norepinephrine ([3H]-NE) uptake and [3H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We then characterized [14C]-tramadol binding in cultured bovine adrenal medullary cells. Tramadol inhibited the desipramine-sensitive uptake of [3H]-NE by the cells in a concentration-dependent manner (50% inhibitory concentration = 21.5 +/- 6.0 microM). Saturation analysis revealed that tramadol increased the apparent Michaelis constant of [3H]-NE uptake without changing the maximal velocity, indicating that inhibition occurred via competition for the NET (inhibition constant, K (i) = 13.7 microM). Tramadol inhibited the specific binding of [3H]-desipramine to plasma membranes. Scatchard analysis of [3H]-desipramine binding revealed that tramadol increased the apparent dissociation constant (K (d)) for binding without altering maximal binding, indicating competitive inhibition (K (i) = 11.2 microM). The binding of [14C]-tramadol to the cells was specific and saturable, with a K (d) of 18.1 +/- 2.4 microM. These findings indicate that tramadol competitively inhibits NET function at desipramine-binding sites. IMPLICATIONS: Tramadol competitively inhibits norepinephrine transporter function at desipramine-binding sites in the adrenal medullary cells and probably the noradrenergic neurons of the descending inhibitory system. |
| tramadol |
mu-opioid-receptor |
True Positive |
16793069 |
Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K: Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology. 2006 Sep;51(3):651-8. Epub 2006 Jun 21. Tramadol is thought to induce analgesia via both opioid and non-opioid pathways, although the precise mechanisms remain to be elucidated. In this study, we investigated the roles of the mu-opioid receptor (MOP) in analgesic and rewarding effects of tramadol by using MOP knockout (KO) mice. Tramadol-induced antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous and homozygous MOP-KO mice when compared with that in wild-type mice. Interestingly, however, tramadol retained its ability to induce significant antinociception in homozygous MOP-KO mice. The tramadol-induced antinociception remaining in homozygous MOP-KO mice was not significantly affected by methysergide, a serotonin receptor antagonist, but was partially blocked by yohimbine, an adrenaline alpha2 receptor antagonist, and both naloxone, a non-selective opioid receptor antagonist, and yohimbine. In addition, antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP-KO mice. On the other hand, neither wild-type nor homozygous MOP-KO mice showed significant place preference for tramadol in a conditioned place preference test, although there were slight tendencies toward preference in wild-type mice and avoidance in homozygous MOP-KO mice. These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha2 receptor mediate most of the analgesic properties of tramadol. |
| tramadol |
mu-opioid-receptor |
True Positive |
15509185 |
Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids. |
| tramadol |
mu-opioid-receptor |
True Positive |
10991912 |
Potschka H, Friderichs E, Loscher W: Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy. Br J Pharmacol. 2000 Sep;131(2):203-12. 1. The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O:-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+/-)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. 2. At doses within the analgesic range, (+/-)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (+/-)-tramadol, generalized seizures were observed at 30 mg kg (-1) in most kindled but not in nonkindled rats. The (-)-enantiomer induced myoclonic seizures at 30 mg kg (-1) in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg (-1). Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3. The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures. |
| tramadol |
mu-opioid-receptor |
True Positive |
10961373 |
Gillen C, Haurand M, Kobelt DJ, Wnendt S: Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol. 2000 Aug;362(2):116-21. The present study was conducted to characterise the centrally active analgesic drug tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)-methyl]-1-(3-methoxyphenyl)-cyclohe xanol hydrochloride] and its metabolites M1, M2, M3, M4 and M5 at the cloned human mu-opioid receptor. Membranes from stably transfected Chinese hamster ovary (CHO) cells were used to determine the four parameters of the ligand-receptor interaction: the affinity of (+/-)-tramadol and its metabolites was determined by competitive inhibition of [3H] naloxone binding under high and low salt conditions. The agonist-induced stimulation of [35S] GTPgammaS binding permits the measurement of potency (EC50), efficacy (Emax = maximal stimulation) and relative intrinsic efficacy (effect as a function of receptor occupation). The metabolite (+)-M1 showed the highest affinity (Ki=3.4 nM) to the human mu-opioid receptor, followed by (+/-)-M5 (Ki=100 nM), (-)-M1 (Ki=240 nM) and (+/-)-tramadol (Ki=2.4 microM). The [35S] GTPgammaS binding assay revealed an agonistic activity for the metabolites (+)-M1, (-)-M1 and (+/-)-M5 with the following rank order of intrinsic efficacy: (+)-M1>(+/-)-M5>(-)-M1. The metabolites (+/-)-M2, (+/-)-M3 and (+/-)-M4 displayed only weak affinity (Ki> 10 microM) and had no stimulatory effect on GTPgammaS binding. These data indicate that the metabolite (+)-M1 is responsible for the mu-opioid-derived analgesic effect. |
| tramadol |
mu-opioid-receptor |
True Positive |
9258310 |
Tobias JD: Seizure after overdose of tramadol. South Med J. 1997 Aug;90(8):826-7. Tramadol (Ultram) is a new analgesic agent with a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of neurotransmitter (serotonin, norepinephrine) re-uptake. Although it has proven to be a safe and effective agent for the control of pain, adverse effects can occur with its use. I report the occurrence of seizure activity after the inadvertent administration of 4 mg/kg of tramadol to a child. Previous reports of seizure activity after tramadol administration are reviewed and the treatment of this problem is discussed. |
| tramadol |
mu-opioid-receptor |
True Positive |
1309873 |
Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL: Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther. 1992 Jan;260(1):275-85. Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects. |
| tramadol |
5-HT1B |
True Positive |
16832657 |
Berrocoso E, Rojas-Corrales MO, Mico JA: Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice. Psychopharmacology. 2006 Sep;188(1):111-8. Epub 2006 Jul 11. RATIONALE: Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical analgesic which binds weakly to i-opioid receptors and enhances the extra-neuronal concentration of noradrenaline and serotonin by interference with both the uptake and release mechanisms. OBJECTIVES: The present study was undertaken to evaluate the potential role of 5-HT1A and 5-HT1B receptors on the analgesic and antidepressant-like effect of tramadol. METHODS: The effect of either a selective 5-HT1A receptor antagonist (WAY 100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexane carboxamide; 0.2-0.8, 8 mg/kg) or a selective 5-HT1B receptor antagonist (SB 216641; N-[3-(3-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1' -biphenyl)-4-carboxamide; 0.2-0.8, 8 mg/kg) was investigated in mice in combination with tramadol by means of the hot-plate test, a phasic nociceptive model, and the forced swimming test, a paradigm aimed at screening potential antidepressants. RESULTS: The results showed that WAY 100635 enhanced the antinociceptive effect and produced a large decrease in the antidepressant-like effect of tramadol. In contrast, SB 216641 did not significantly modify either the analgesic or the antidepressant-like effects of tramadol. CONCLUSIONS: These findings suggest that 5-HT1A receptors modulate the analgesic and the antidepressant-like effects of tramadol in differing ways. The results suggest the involvement of the 5-HT1A autoreceptors from the raphe nuclei and spinal 5-HT1A receptors in the antinociceptive effect. In contrast, the 5-HT1A receptors located in the forebrain may be responsible for the blockade of the antidepressant-like effect of tramadol. 5-HT1B receptors seem not to modify these effects in the models investigated. |
| tramadol |
5-HT1B |
True Positive |
15777775 |
Rojas-Corrales MO, Berrocoso E, Mico JA: Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol. Eur J Pharmacol. 2005 Mar 21;511(1):21-6. Tramadol, (1RS,2RS)-2-[(dimethylamine)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) in the raphe nucleus. We have previously demonstrated that pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine (1A/1B) receptor antagonist, enhanced tramadol antinociception and that the selective 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) reduced it. These effects were related to the negative feedback control that regulates raphe region neurones. The current study examines the ability of the selective antagonist at somatodendritic 5-HT1A receptors, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY100635, 0.8 mg/kg), the selective antagonist at terminal 5-HT1B receptors, N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1' -biphenyl)-4-carboxamide (SB216641, 0.1-0.8 mg/kg) and the selective agonist at 5-HT1B receptors, 1,4-tDihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b] pyridin-5-one (CP93129, 0.2-0.4 mg/kg), to modify the antinociceptive effect of 4-64 mg/kg of tramadol in the hot plate test in mice. The results show that 0.8 mg/kg of WAY100635 enhanced antinociceptive effect of tramadol while neither agonism nor antagonism at the 5-HT1B receptor modifies it significantly at the doses tested. These results account for involvement of the somatodendritic 5-HT1A receptors in the analgesic effect of tramadol and support the supraspinal interaction of serotonin and the opioid system in the regulation of pain. |
| tramadol |
prodynorphin |
False Positive |
17401159 |
Candeletti S, Lopetuso G, Cannarsa R, Cavina C, Romualdi P: Effects of prolonged treatment with the opiate tramadol on prodynorphin gene expression in rat CNS. J Mol Neurosci. 2006;30(3):341-7. A low abuse liability is reported for tramadol, an analgesic drug centrally acting through either opioid or nonopioid mechanisms. In this paper, we evaluated the effects of the repeated administration (7 d) of different doses of tramadol (10, 20, and 80 mg/kg, intraperitoneally) on the opioid precursor prodynorphin biosynthesis, in comparison with morphine (10 mg/kg, intraperitoneally), in the rat central nervous system (CNS). Northern analysis showed that morphine and tramadol produced different effects. While morphine caused a downregulation of prodynorphin mRNA levels in all investigated areas (hypothalamus, hippocampus, and striatum), tramadol did not cause any significant change in the striatum, and did not decrease prodynorphin biosynthesis in the hypothalamus and in the hippocampus, at nontoxic doses (10 and 20 mg/kg). The highest dose of tramadol (80 mg/kg) decreased prodynorphin mRNA levels in the hypothalamus and the hippocampus but not in the striatum. These data give some information on tramadol effects at molecular level in the CNS. They indicate that the alterations of prodynorphin gene expression caused by tramadol and morphine show a different pattern that may be related to the different abuse potential of the two analgesic drugs. |
| tramadol |
substance-p |
True Positive |
17367519 |
Herbert MK, Weis R, Holzer P: The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms. Can J Physiol Pharmacol. 2005 Dec;83(12):1137-45. BACKGROUND: Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. Although tramadol is an opioid-like analgesic, its effect on gut motility is little known. Therefore, the effect of (+)-tramadol, (-)-tramadol and the major metabolite O-desmethyltramadol on intestinal peristalsis in vitro and their mechanisms of action were examined. Distension-induced peristalsis was recorded in fluid-perfused segments of the guinea pig small intestine. The intraluminal peristaltic pressure threshold (PPT) was used to quantify the motor effects of extraserosally administered drugs. RESULTS: Racemic tramadol, its (+)- and (-)-enantiomers and the major metabolite O-desmethyltramadol (0.1-100 microM) concentration-dependently increased PPT until peristalsis was transiently or persistently abolished. The rank order of potency was (-)-tramadol < (+)-tramadol caused by (+)- and (-)-tramadol was markedly and that of O-desmethyltramadol nearly completely prevented by naloxone, but left unaltered by the 5-hydroxytryptamine receptor antagonists methysergide plus tropisetron. The adrenoceptor antagonists prazosin plus yohimbine reduced the effect of (+)- and (-)-tramadol but not that of O-desmethyltramadol. CONCLUSION: The results show that the metabolite O-desmethyltramadol is more potent in inhibiting peristalsis than its parent compound. The action of all tramadol forms depends on opioid receptors, and that of (+)- and (-)-tramadol also involves adrenoceptors. |
| tramadol |
C-reactive-protein |
True Positive |
17175820 |
El-Sharrawy EA, El-Hakim IE, Sameeh E: Attenuation of C-reactive protein increases after exodontia by tramadol and ibuprofen. Anesth Prog. 2006 Fall;53(3):78-82. The anti-inflammatory effects of ibuprofen and tramadol were investigated by measuring C-reactive protein concentrations after removal of an impacted lower third molar. Forty-five American Society of Anesthesiologists Class I patients were randomly categorized into 3 equal groups according to postoperative analgesic medication. The first group received tramadol (100 mg every 8 hours), the second group received ibuprofen (400 mg every 8 hours), and the last group received half doses of both drugs in combination (50 mg tramadol every 8 hours and 200 mg ibuprofen every 8 hours). C-reactive protein was measured before surgery to exclude the presence of any preexisting inflammatory condition that might interfere with the study. C-reactive protein was also determined immediately after surgery and 72 hours postoperatively. At 72 hours, C-reactive protein had increased over postsurgery baseline by 123% in the tramadol group (P < .001), 84% in the ibuprofen group (P < .001), and only 37% in the combined analgesic group (P = .078). These results suggest that tramadol may produce supra-additive anti-inflammatory effects with ibuprofen after third-molar extractions. |
| tramadol |
GTP-binding-protein |
False Positive |
11561087 |
Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A: Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther. 2001 Oct;299(1):255-60. Tramadol is a widely used, centrally acting analgesic, but its mechanisms of action are not completely understood. Muscarinic receptors are known to be involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. This study investigated the effects of tramadol on muscarinic receptors by using two different systems, i.e., a Xenopus laevis oocyte expression system and cultured bovine adrenal medullary cells. Tramadol (10 nM-100 microM) inhibited acetylcholine-induced currents in oocytes expressing the M1 receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. On the other hand, tramadol did not inhibit the current induced by AlF4-, a direct activator of GTP-binding protein. In cultured bovine adrenal medullary cells, tramadol (100 nM-100 microM) suppressed muscarine-induced cyclic GMP accumulation. Moreover, tramadol inhibited the specific binding of [3H] quinuclidinyl benzilate (QNB). Scatchard analysis showed that tramadol increases the apparent dissociation constant (Kd) value without changing the maximal binding (Bmax), indicating competitive inhibition. These findings suggest that tramadol at clinically relevant concentrations inhibits muscarinic receptor function via QNB-binding sites. This may explain the neuronal function and anticholinergic effect of tramadol. |
| tramadol |
CYP2B6 |
False Positive |
11454734 |
Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG: Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos. 2001 Aug;29(8):1146-55. The metabolism of cis-tramadol has been studied in human liver microsomes and in cDNA-expressed human cytochrome P-450 (CYP) isoforms. Human liver microsomes catalyzed the NADPH-dependent metabolism of tramadol to the two primary tramadol metabolites, namely, O-desmethyl-tramadol (metabolite M1) and N-desmethyl-tramadol (metabolite M2). In addition, tramadol was also metabolized to two minor secondary metabolites (each comprising < or =3.0% of total tramadol metabolism), namely, N,N-didesmethyl-tramadol (metabolite M3) and N,O-didesmethyl-tramadol (metabolite M5). Kinetic analysis revealed that multiple CYP enzymes were involved in the metabolism of tramadol to both M1 and M2. For the high-affinity enzymes involved in M1 and M2 formation, K (m) values were 116 and 1021 microM, respectively. Subsequent reaction phenotyping studies were performed with a tramadol substrate concentration of 250 microM. In studies with characterized human liver microsomal preparations, good correlations were observed between tramadol metabolism to M1 and M2 and enzymatic markers of CYP2D6 and CYP2B6, respectively. Tramadol was metabolized to M1 by cDNA-expressed CYP2D6 and to M2 by CYP2B6 and CYP3A4. Tramadol metabolism in human liver microsomes to M1 and M2 was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. In summary, this study demonstrates that cis-tramadol can be metabolized to tramadol metabolites M1, M2, M3, and M5 in human liver microsomal preparations. By kinetic analysis and the results of the reaction phenotyping studies, tramadol metabolism in human liver is catalyzed by multiple CYP isoforms. Hepatic CYP2D6 appears to be primarily responsible for M1 formation, whereas M2 formation is catalyzed by CYP2B6 and CYP3A4. |
| tramadol |
acetylcholine-receptors |
True Positive |
17380034 |
Minami K, Uezono Y, Ueta Y: Pharmacological aspects of the effects of tramadol on G-protein coupled receptors. J Pharmacol Sci. 2007 Mar;103(3):253-60. Tramadol is an analgesic that is used worldwide, but its mechanisms of action have not been elucidated. It has been speculated that tramadol acts primarily through the activation of micro-opioid receptors and the inhibition of monoamine reuptake. The majority of studies to date have focused on ion channels in the central nervous system as targets of anesthetics and analgesics. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for analgesics and anesthetics. In particular, tramadol has been shown to affect GPCRs, including muscarinic acetylcholine receptors and 5-hydroxytryptamine receptors. Here, the effects of tramadol on monoamine transporters, GPCRs, and ion channels are presented, and recent research on the pharmacology of tramadol is discussed. |
| tramadol |
acetylcholine-receptors |
True Positive |
16296359 |
Mimami K: [Recent evidences in the pharmacological mechanisms of the tramadol] . Masui. 2005 Nov;54(11):1224-33. Tramadol [(1R, 2R) and (1S, 2S)-2-dimethyl-amino-methyl-1-(3-methoxyphenyl) -cyclohexanol hydrochloride] has been used clinically. It binds to micro-opioid receptors with lower affinity than morphine, which suggests that the antinociceptive action of tramadol may not be due to opioid receptor binding. Several lines of evidence have shown that tramadol inhibits the reuptake of monoamines, as do antidepressant drugs such as desipramine. Tramadol inhibits the reuptake of NE and serotonin. The mechanisms of action of tramadol have not been well understood. Recently, some evidences in the mechanisms of action of tramadol have been published. Tramadol inhibits the muscarinic receptor, serotonin receptor, and nicotinic acetylcholine receptor ion-channel, suggesting these receptors might be related to the mechanisms of action of tramadol. In this review, the mechanisms of action of tramadol were reviewed form these findings. Tramadol does not alter renal blood flow (RBF) in normal rats. This suggests that tramadol would be a safe analgesic maintaining RBF during the postoperative period. It would be necessary to study the effects of tramadol on orphan G-ptotein coupled receptor which is related to the pain. |
| pefloxacin |
IFN-gamma |
True Positive |
8673851 |
Zucca M, Millesimo M, Giovarelli M, Diverio D, Musso T, Savoia D: Protective role of the pefloxacin-IFN-gamma association in Leishmania major-infected mice. New Microbiol. 1996 Jan;19(1):39-46. Four groups of female Balb/c mice were inoculated in the left hind footpad with 30 microliters of RPMI 1640 medium containing 10 (7) Leishmania major amastigotes/ml. One group was injected sc with 200 microliters of RPMI 1640 containing 180 micrograms of pefloxacin for 20 days, a second group with the same amount of medium containing 100 units of recombinant murine interferon gamma (rmIFN-gamma). The third group was treated with the association, while the fourth group received plain medium in an identical regimen. Pefloxacin or IFN-gamma significantly decreased the size of primary lesions, while their association was significantly more efficient in this respect, in reducing the incidence of metastatic lesions, and in clearing parasites from the spleen. We also investigated the effect of pefloxacin on the activation of mouse spleen cells by Concanavalin A (Con A) in vitro, without detecting any interference on the proliferative response or IFN-gamma production. |
| pefloxacin |
P-glycoprotein |
False Positive |
11250882 |
Tsai TH: Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P-glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis. Br J Pharmacol. 2001 Mar;132(6):1310-6. 1. In vivo microdialysis with HPLC was used to investigate the pharmacokinetics of pefloxacin and its interaction with cyclosporin A. Microdialysis probes were inserted into the jugular vein/right atrium, the striatum and the bile duct of male Sprague-Dawley rats. Biological fluid sampling thereby allowed the simultaneous determination of pefloxacin levels in blood, brain and bile. 2. Following pefloxacin administration, the brain-to-blood coefficient of distribution was 0.036. This was calculated by dividing the area under the concentration curve (AUC) of pefloxacin in brain by its AUC in blood (k=AUC (brain)/AUC (blood)). 3. When the P-glycoprotein cyclosporin A (10 mg kg (-1)) was co-administered with pefloxacin (10 mg kg (-1)), the AUC and the mean residence time in rat blood did not differ significantly (P> 0.05). Similarly, the pharmacokinetics of pefloxacin in rat brain was not affected by the presence of cyclosporin A. 4. The AUC of unbound pefloxacin in bile was significantly greater than that in blood. The disposition of pefloxacin in rat bile shows a slow elimination phase following a peak concentration 30 min after pefloxacin administration (10 mg kg (-1), i.v.). The bile-to-blood coefficient of distribution (k=AUC (bile)/AUC (blood)) was 1.53. 5. The results indicated that pefloxacin was able to penetrate the blood-brain barrier and that the concentration in bile was greater than that in the blood, suggesting active biliary excretion of pefloxacin. Current data obtained from rats show no significant impact of cyclosporin A on the pharmacokinetics of pefloxacin in rat blood and brain when administered by concomitant i.v. bolus. |
| pefloxacin |
phospholipase-C |
True Positive |
9122276 |
Hybenova D, Majtan V: The influence of postantibiotic effects and postantibiotic effects of sub-inhibitory concentrations of quinolones and aminoglycosides on phospholipase C of Pseudomonas aeruginosa. Pharmazie. 1997 Feb;52(2):157-9. We have studied the postantibiotic effect (PAE) and postantibiotic sub-MICs effect (PA SME) of ciprofloxacin, pefloxacin, netilmicin and tobramycin on the production of phospholipase C (PLC) in a Pseudomonas aeruginosa strain isolated from clinical material. All antibiotics tested (postantibiotic phase evoked by 2.MIC) reduced the production of PLC, particularly pefloxacin to 13.2%. The PA phase evoked by 4.MIC of quinolones did not cause regrowth of P. aeruginosa and aminoglycosides inhibited PLC, in particular with tobramycin to 16.9%. The effect of PA SME (2.MIC) of netilmicin and tobramycin inhibited PLC more expressively (< 20%) than ciprofloxacin; pefloxacin did not allow regrowth. PA SMEs of the antibiotics tested reduced the production of PLC more effectively than PAE. |
| pefloxacin |
immunoglobulin |
True Positive |
2846490 |
Fantoni M, Tamburrini E, Pallavicini F, Antinori A, Nervo P: Influence of ofloxacin and pefloxacin on human lymphocyte immunoglobulin secretion and on polymorphonuclear leucocyte superoxide anion production. J Antimicrob Chemother. 1988 Aug;22(2):193-6. The influence of two fluoroquinolone derivatives, ofloxacin and pefloxacin, on lymphocyte immunoglobulin secretion and on polymorphonuclear leucocyte superoxide anion production was assessed. Pharmacological concentrations did not influence the studied functions, while suprapharmacological concentrations decreased immunoglobulin production. |
| pefloxacin |
tumor-necrosis-factor |
True Positive |
9869897 |
Puc J, Kwiatkowski P, Pacanowski J, Rotbart-Fiedor M, Wardawa A, Mazurek AP, Rowinski W, Hardy MA, Fiedor P: Mitochondrial activity after cold preservation of pancreatic islet cells treated with pefloxacin (PFX). Ann Transplant. 1998;3(1):38-41. Mitochondrial energetic and oxidative dysfunctions caused by free radical production trigger release of proinflammatory cytokines involved in organ rejection. The aim of this study was to investigate the role of a fluoroquinolone drug, pefloxacin (PFX) and those of various cold preservation solutions on pancreatic beta cell viability. Our data clearly demonstrate that islet cell viability, as determined by glucose-stimulated insulin secretion, is directly correlated with reduced expression of microsomal cytochrome P-450IIIA. Moreover, IL-2, a known mediator of apoptosis was found to be downregulated, whereas TNF-alpha had been upregulated for the first 18 hours after pefloxacin administration. These results demonstrate that pefloxacin downregulates the expression of cytochrome P-450IIIA isozyme and regulates the production of TNF-alpha and IL-2. Thus, we postulate that the presence of pefloxacin in the pancreatic islet cells before organ preservation facilitates increased cell viability. |
| pefloxacin |
decorin |
True Positive |
9733283 |
Bernard-Beaubois K, Hecquet C, Hayem G, Rat P, Adolphe M: In vitro study of cytotoxicity of quinolones on rabbit tenocytes. Cell Biol Toxicol. 1998 Aug;14(4):283-92. Tendinitis and tendon rupture complicating fluoroquinolone therapy have been reported recently, especially affecting men over 60 years. These new quinolones are more potent antimicrobial agents than older nonfluorinated compounds like nalidixic acid. We compared the effects of one quinolone (nalidixic acid) and two fluoroquinolones (norfloxacin and pefloxacin) on cultured rabbit Achilles tendon cells. First, we examined their effects on cell viability, mitochondrial succinate dehydrogenase and global activity, mitochondrial activity using microtitration methods. Pefloxacin and norfloxacin were more cytotoxic than nalidixic acid according to IC50 values. These results confirm that mitochondria represent a biological target of fluoroquinolones. Moreover, the extracellular matrix was studied by molecular hybridization. After a 72 h treatment, the level of type I collagen transcripts was not modified with any of the three antimicrobial agents, whereas mRNA encoding decorin was decreased with 10 (-4) mol/L pefloxacin only. The decrease of transcripts encoding decorin suggests that this matrix component is another target of pefloxacin and modification of decorin seems to be an early event (before mitochondrion alteration) which may contribute to the explanation of tendon rupture. |
| pefloxacin |
lactoferrin |
True Positive |
16691639 |
Fan JC, Chen X, Wang Y, Fan CP, Shang ZC: Binding interactions of pefloxacin mesylate with bovine lactoferrin and human serum albumin. J Zhejiang Univ Sci B. 2006 Jun;7(6):452-8. The binding of pefloxacin mesylate (PFLX) to bovine lactoferrin (BLf) and human serum albumin (HSA) in dilute aqueous solution was studied using fluorescence spectra and absorbance spectra. The binding constant K and the binding sites n were obtained by fluorescence quenching method. The binding distance r and energy-transfer efficiency E between pefloxacin mesylate and bovine lactoferrin as well as human serum albumin were also obtained according to the mechanism of Forster-type dipole-dipole nonradiative energy-transfer. The effects of pefloxacin mesylate on the conformations of bovine lactoferrin and human serum albumin were also analyzed using synchronous fluorescence spectroscopy. |
| pefloxacin |
interleukin-2 |
True Positive |
9869897 |
Puc J, Kwiatkowski P, Pacanowski J, Rotbart-Fiedor M, Wardawa A, Mazurek AP, Rowinski W, Hardy MA, Fiedor P: Mitochondrial activity after cold preservation of pancreatic islet cells treated with pefloxacin (PFX). Ann Transplant. 1998;3(1):38-41. Mitochondrial energetic and oxidative dysfunctions caused by free radical production trigger release of proinflammatory cytokines involved in organ rejection. The aim of this study was to investigate the role of a fluoroquinolone drug, pefloxacin (PFX) and those of various cold preservation solutions on pancreatic beta cell viability. Our data clearly demonstrate that islet cell viability, as determined by glucose-stimulated insulin secretion, is directly correlated with reduced expression of microsomal cytochrome P-450IIIA. Moreover, IL-2, a known mediator of apoptosis was found to be downregulated, whereas TNF-alpha had been upregulated for the first 18 hours after pefloxacin administration. These results demonstrate that pefloxacin downregulates the expression of cytochrome P-450IIIA isozyme and regulates the production of TNF-alpha and IL-2. Thus, we postulate that the presence of pefloxacin in the pancreatic islet cells before organ preservation facilitates increased cell viability. |
| pefloxacin |
Interleukin-1 |
True Positive |
3496323 |
Roche Y, Fay M, Gougerot-Pocidalo MA: Effects of quinolones on interleukin 1 production in vitro by human monocytes. Immunopharmacology. 1987 Apr;13(2):99-109. The new quinoline derivative antibiotics (quinolones), pefloxacin and ciprofloxacin at concentrations higher than 50 micrograms/ml inhibit the PHA response of the human mononuclear leukocytes in vitro. Since monocytes have been shown to be accessory cells for the activation of lymphocytes by mitogens, we investigated the effects of pefloxacin and ciprofloxacin on extracellular interleukin 1 (IL-1) and cell-associated IL-1 from lipopolysaccharide-stimulated human monocytes. Pefloxacin and ciprofloxacin decreased the extracellular IL-1 in a dose-dependent manner, while cell-associated IL-1 was not altered. These effects were observed even after a short period of incubation (1 or 2 h). No inhibitory activity against purified IL-1 or IL-2 could be demonstrated in the dialyzed supernatants from pefloxacin- or ciprofloxacin-treated monocytes. Neither pefloxacin nor ciprofloxacin modified the biological activity of preformed IL-1. The decrease of extracellular IL-1 induced by pefloxacin and ciprofloxacin could, in part, account for the observed decrease in the proliferative response of human mononuclear leukocytes to phytohemagglutinin, as extracellular IL-1 and proliferative response were positively correlated (at various concentrations of pefloxacin and ciprofloxacin). The decrease in extracellular IL-1 was not associated with any alteration in the expression of the HLA-DR antigen on the monocytes membrane. These data suggested that pefloxacin and ciprofloxacin could antagonize IL-1 production and release by lipopolysaccharide-stimulated monocytes. These quinolones could be interesting tools to study the production, processing, transport and release from the monocytes of IL-1. |
| pefloxacin |
Interleukin-1 |
True Positive |
3325909 |
Roche Y, Pocidalo JJ, Gougerot-Pocidalo MA: [Effect of antibiotics on IL-1 in vitro production by human monocytes] . Pathol Biol. 1987 Dec;35(10 Pt 2):1422-5. The effects of penicillin, macrolides (spiramycin and erythromycin), cephalosporins (cefaclor and cefadroxil), cycline (doxycycline) and quinolones (pefloxacin, ciprofloxacin and ofloxacin) on extracellular and cell-associated interleukin-1 activity from human monocytes were investigated in vitro. When cells were treated with 10 micrograms/ml of quinolones, cephalosporins or penicillin, no effect on IL-1 production could be detected. Using 100 micrograms/ml, extracellular IL-1 activity was found to be decreased by quinolones (about 35% of the control without antibiotic) without modification of the cell-associated IL-1 activity. Extra and intracellular IL-1 was only slightly decreased by cephalosporins, while penicillin did not alter the IL-1 activities. Spiramycin and doxycycline using 100 micrograms/ml increased extracellular IL-1 while cell-associated was decreased. A toxic effect may have been exerted by these antimicrobial agents. |
| pefloxacin |
Interleukin-1 |
True Positive |
3260587 |
Roche Y, Fay M, Gougerot-Pocidalo MA: Interleukin-1 production by antibiotic-treated human monocytes. J Antimicrob Chemother. 1988 May;21(5):597-607. The effects of penicillin, macrolides (spiramycin and erythromycin), cephalosporins (cefaclor and cefadroxil), tetracycline (doxycycline) and quinolones (pefloxacin, ciprofloxacin and ofloxacin) on extracellular and cell-associated interleukin 1 (IL-1) activity from human adherent mononuclear leucocyte cells were investigated in vitro. When cells were treated with an antibiotic concentration of 10 mg/l, no apparent effect could be detected for penicillin, erythromycin, cephalosporins or quinolones, while a slight increase of extracellular IL-1 activity associated with a decrease of intracellular IL-1 activity was observed with spiramycin and doxycycline. When high antibiotic concentration were used, extracellular IL-1 activity was increased by macrolides and tetracycline, while both cell-associated and class II human monocyte antigen expression were decreased. A toxic effect may have been exerted by these antimicrobial agents, since cell viability was altered when they were used at high concentrations. In contrast, extracellular IL-1 activity was found to be decreased by quinolones and cephalosporins. Intracellular IL-1 activity was also decreased by cephalosporins, while quinolones did not modify either cell-associated IL-1 activity or class II human monocyte antigen expression. The effect induced by quinolones and cephalosporins occurred without modification of cell viability. IL-1 activity was shown to be affected by antibiotics over the same range of concentrations which are known to inhibit mononuclear leucocyte proliferation. Our data may help in defining the mechanism by which the mitogen-induced mononuclear proliferative response is suppressed by antimicrobial agents since this appears to involve the inhibition of IL-1 production or of its release. |
| pefloxacin |
serum-albumin |
True Positive |
9024831 |
Galdbart JO, Branger C, Andreassian B, Lambert-Zechovsky N, Kitzis M: Elution of six antibiotics bonded to polyethylene vascular grafts sealed with three proteins. J Surg Res. 1996 Dec;66(2):174-8. The elution of six antistaphylococcal antibiotics from vascular polyethylene grafts sealed with albumin, gelatin, or collagen were studied in an in vitro system. The antibiotics tested were pefloxacin, vancomycin, teicoplanin, fusidic acid, pristinamycin, and rifampicin. The grafts were impregnated by simple soaking in antibiotic (1 mg/ml). The data were fitted to an exponential model and antibiotic half-lives (t1/2) were calculated from the regression lines. All the antibiotics tested were bound to the protein sealants. Antibiotic release varied with the type of antibiotic and the sealant. Rifampicin was eluted most slowly, particularly with albumin- and gelatin-sealed grafts, with t1/2 at 4-5.5 hr and antibiotic activity was still found at 48 hr. The glycopeptides were also eluted more slowly from albumin or gelatin sealant than from collagen. Although large quantities of glycopeptides were initially bound, they were quickly eluted (t1/2 = 30-44 min) and there was no residual antibiotic activity at 24 hr. Pefloxacin, pristinamycin, and fusidic acid bound to collagen or gelatin sealants were the most rapidly eluted, with t1/2 of 3-14 min, but they were eluted more slowly from albumin-sealed grafts, with t1/2 of 22-90 min. In vitro studies can be useful for evaluating the binding of antibiotics to protein-sealed grafts before animal experiments or human testing. |
| pefloxacin |
collagen |
True Positive |
10722483 |
Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B: Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen. Antimicrob Agents Chemother. 2000 Apr;44(4):867-72. Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen. |
| pefloxacin |
collagen |
True Positive |
10582882 |
Simonin MA, Gegout-Pottie P, Minn A, Gillet P, Netter P, Terlain B: Proteoglycan and collagen biochemical variations during fluoroquinolone-induced chondrotoxicity in mice. Antimicrob Agents Chemother. 1999 Dec;43(12):2915-21. Although fluoroquinolone antibacterials have a broad therapeutic use, with a relatively low incidence of severe side effects, they have been reported to induce lesions in the cartilage of growing animals by a mechanism that remains unclear. This study was undertaken to determine the potentially deleterious effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations in levels of proteoglycan anabolism measured by in vivo [(35) S] sulfate incorporation into cartilage and oxidative modifications of collagen assessed by detection of carbonyl derivatives were monitored after administration of pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly decreased the rate of biosynthesis of proteoglycan for the first 24 h. However, no difference was observed after 48 h. The decrease in proteoglycan synthesis was accompanied by a marked drop in serum sulfate concentration and a concomitant increase in urinary sulfate excretion. The decrease in proteoglycan synthesis, also observed ex vivo, may suggest a direct effect of pefloxacin on this process, rather than it being a consequence of a low concentration of sulfate. On the other hand, treatment with pefloxacin for 10 days induced oxidative damage to collagen. In conclusion, this study demonstrates, for the first time, that pefloxacin administration to mice leads to modifications in the metabolism and integrity of extracellular proteins, such as collagen and proteoglycans, which may account for the side effects observed. These results offer new insights to explain quinolone-induced disorders in growing articular cartilage. |
| pefloxacin |
collagen |
True Positive |
9024831 |
Galdbart JO, Branger C, Andreassian B, Lambert-Zechovsky N, Kitzis M: Elution of six antibiotics bonded to polyethylene vascular grafts sealed with three proteins. J Surg Res. 1996 Dec;66(2):174-8. The elution of six antistaphylococcal antibiotics from vascular polyethylene grafts sealed with albumin, gelatin, or collagen were studied in an in vitro system. The antibiotics tested were pefloxacin, vancomycin, teicoplanin, fusidic acid, pristinamycin, and rifampicin. The grafts were impregnated by simple soaking in antibiotic (1 mg/ml). The data were fitted to an exponential model and antibiotic half-lives (t1/2) were calculated from the regression lines. All the antibiotics tested were bound to the protein sealants. Antibiotic release varied with the type of antibiotic and the sealant. Rifampicin was eluted most slowly, particularly with albumin- and gelatin-sealed grafts, with t1/2 at 4-5.5 hr and antibiotic activity was still found at 48 hr. The glycopeptides were also eluted more slowly from albumin or gelatin sealant than from collagen. Although large quantities of glycopeptides were initially bound, they were quickly eluted (t1/2 = 30-44 min) and there was no residual antibiotic activity at 24 hr. Pefloxacin, pristinamycin, and fusidic acid bound to collagen or gelatin sealants were the most rapidly eluted, with t1/2 of 3-14 min, but they were eluted more slowly from albumin-sealed grafts, with t1/2 of 22-90 min. In vitro studies can be useful for evaluating the binding of antibiotics to protein-sealed grafts before animal experiments or human testing. |
| pefloxacin |
cytochrome-P-450 |
True Positive |
10096258 |
Kinzig-Schippers M, Fuhr U, Zaigler M, Dammeyer J, Rusing G, Labedzki A, Bulitta J, Sorgel F: Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2. Clin Pharmacol Ther. 1999 Mar;65(3):262-74. BACKGROUND AND OBJECTIVES: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2. METHODS: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme (s) that mediate pefloxacin N-4'-demethylation with selective inhibitors. RESULTS: For the in vivo study, ANOVA-based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steadystate plasma concentrations (Cmax,ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation. CONCLUSIONS: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin. |
| pefloxacin |
LDH-X |
True Positive |
10623489 |
Abd-Allah AR, Aly HA, Moustafa AM, Abdel-Aziz AA, Hamada FM: Adverse testicular effects of some quinolone members in rats. Pharmacol Res. 2000 Feb;41(2):211-9. In the last few years, a marked decrease in male fertility has been reported. Environmental factors were recently suspected for this effect. Among those factors is the misuse of drugs and in particular antibiotics. Quinolones are a group of antibacterial agents with broad-spectrum activity. Testicular impairment of some quinolone members is controversial; a matter which stimulated our attention to investigate the adverse testicular effects of the most familiar quinolone members, namely: ofloxacin, ciprofloxacin and pefloxacin. They were given to rats in doses of 72, 135 and 72 mg kg (-1) day (-1) p.o., respectively, for 15 consecutive days. Ofloxacin was also used to establish a dose-response relationship in doses of 36, 72 and 360 mg kg (-1) day (-1) p.o. for 15 consecutive days. Results revealed that ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm count, motility and daily sperm production were markedly decreased. Ofloxacin induced a dose-dependent decrease in testicular LDH-X activity, sperm count and motility. Furthermore, daily sperm production showed a marked reduction which amounted to 26.1% and 40. 0% following administration of ofloxacin (72, 360 mg kg (-1) day (-1) x 15 days), respectively. Moreover, administration of ofloxacin resulted in marked testicular histopathological changes. It is concluded that, ofloxacin, ciprofloxacin and pefloxacin significantly impaired both testicular function and structure in rats. |
| pefloxacin |
CYP1A2 |
True Positive |
12110375 |
Labedzki A, Buters J, Jabrane W, Fuhr U: Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2. Biochem Pharmacol. 2002 Jun 15;63(12):2159-67. For the characterisation of murine models of CYP1A2 mediated metabolism in humans we compared the metabolism of caffeine and paraxanthine in human liver microsomes (LM) (two samples) and in LM from CYP1A2-null and wild-type mice. Inhibition experiments were carried out with the quinolones norfloxacin and pefloxacin and the substrate, caffeine. Additionally, in vivo pharmacokinetics of paraxanthine was determined in CYP1A2-null and wild-type mice. All LM produced the primary metabolites of caffeine and paraxanthine. In human LM, the main metabolite of caffeine was paraxanthine (K (M) 0.4 and 0.5 mmol L (-1)). In wild-type and CYP1A2-null mice LM, the main caffeine metabolite was 1,3,7-trimethylurate, but formation was not saturable. Apparent K (M) for paraxanthine formation from caffeine in wild-type and CYP1A2-null murine LM were 0.2 and 4.9 mmol L (-1), respectively. The main metabolite of paraxanthine was 1-methylxanthine in human (K (M) 0.13 and 0.2 mmol L (-1)) and in wild-type mice LM (K (M) 0.53 mmol L (-1)). In CYP1A2-null murine LM, the main paraxanthine metabolite was 7-methylxanthine. The quinolones competitively inhibited caffeine metabolism in human but not in wild-type or CYP1A2-null murine LM. No obvious differences were seen for blood pharmacokinetics and urinary metabolite excretion of paraxanthine between CYP1A2-null and wild-type mice. Thus, for paraxanthine, norfloxacin and pefloxacin interaction with CYP1A2 there were clear differences between mice and man. Our results suggest that an interspecies comparison is required for the metabolism of individual xenobiotics interacting with CYP1A2 prior to the use of mice models to predict its toxicity and/or pharmacological activity in man. |
| pefloxacin |
CYP1A2 |
True Positive |
10096258 |
Kinzig-Schippers M, Fuhr U, Zaigler M, Dammeyer J, Rusing G, Labedzki A, Bulitta J, Sorgel F: Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2. Clin Pharmacol Ther. 1999 Mar;65(3):262-74. BACKGROUND AND OBJECTIVES: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2. METHODS: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme (s) that mediate pefloxacin N-4'-demethylation with selective inhibitors. RESULTS: For the in vivo study, ANOVA-based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steadystate plasma concentrations (Cmax,ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation. CONCLUSIONS: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin. |
| tizanidine |
cytochrome-P450 |
True Positive |
15592331 |
Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ: Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004 Dec;76(6):598-606. BACKGROUND AND OBJECTIVE: Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. RESULTS: Ciprofloxacin increased the area under the plasma concentration-time curve from time 0 to infinity [AUC (0-infinity)] of tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (-35 mm Hg versus -15 mm Hg, P = .001), diastolic blood pressure (-24 mm Hg versus -11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC (0-infinity) of tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. CONCLUSIONS: Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
17618427 |
Karjalainen MJ, Neuvonen PJ, Backman JT: Tolfenamic acid is a potent CYP1A2 inhibitor in vitro but does not interact in vivo: correction for protein binding is needed for data interpretation. Eur J Clin Pharmacol. 2007 Jul 6;. OBJECTIVE: Our aim was to correlate the in vitro and in vivo CYP1A2 inhibition potential of tolfenamic acid, an NSAID highly (99.7%) bound to plasma proteins, to study the significance of protein binding of inhibitor in metabolic drug interactions. METHODS: The effect of tolfenamic acid on CYP1A2 (phenacetin O-deethylation) was studied using human liver microsomes, with and without albumin (0-10 mg/ml). In a randomized, crossover study, 10 volunteers took 200 mg tolfenamic acid or placebo t.i.d. for 3 days. On day 2, a caffeine test was performed. On day 3, each ingested 4 mg of the CYP1A2 substrate tizanidine. Plasma tizanidine, its metabolites (M) and tolfenamic acid, and pharmacodynamic variables were measured. RESULTS: Tolfenamic acid strongly inhibited phenacetin-O-deethylation in vitro (IC (50) 1.8 muM without albumin). Albumin decreased its inhibitory effect in a concentration-dependent manner; the IC (50) exceeded 100 muM with 10 mg/ml of albumin. Tolfenamic acid had no effect on the area under the concentration-time curve [Formula: see text], peak concentration, time of peak concentration or half-life of tizanidine or M-3; only the [Formula: see text] of secondary metabolite M-4 was slightly decreased (13%, P = 0.004). The caffeine test and the pharmacodynamic effects of tizanidine were unchanged. CONCLUSIONS: Tolfenamic acid potently inhibits CYP1A2 in vitro when studied without albumin, but not in vivo. This apparent discrepancy is due to the high protein binding of tolfenamic acid. To avoid overestimation of the interaction potential, the inhibitory effect of highly albumin-bound compounds should also be studied in vitro with albumin, or their exact unbound plasma concentration should be used in predictions. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
16985100 |
Karjalainen MJ, Neuvonen PJ, Backman JT: Rofecoxib is a potent, metabolism-dependent inhibitor of CYP1A2: implications for in vitro prediction of drug interactions. Drug Metab Dispos. 2006 Dec;34(12):2091-6. Epub 2006 Sep 19. Rofecoxib was recently found to greatly increase plasma concentrations of the CYP1A2 substrate drug tizanidine in humans, but there are no published in vitro studies on the CYP1A2-inhibiting effects of rofecoxib. Our objective was to investigate whether rofecoxib is a direct-acting or metabolism-dependent inhibitor of CYP1A2 in vitro. The effect of rofecoxib on the O-deethylation of phenacetin (20 microM) was studied using human liver microsomes. The effect of preincubation time on the inhibitory potential of rofecoxib was also studied, and the inhibitor concentration that supports half the maximal rate of inactivation (KI) and the maximal rate of inactivation (kinact) were determined. Rofecoxib moderately inhibited phenacetin O-deethylation (IC50 23.0 microM), and a 30-min preincubation with microsomes and NADPH considerably increased its inhibitory effect (IC50 4.2 microM). Inactivation of CYP1A2 by rofecoxib required NADPH, and was characterized by a KI of 4.8 microM and a kinact of 0.07 min (-1). Glutathione, superoxide dismutase, mannitol, or dialysis could not reverse the inactivation of CYP1A2 caused by rofecoxib. Fluvoxamine decreased the rofecoxib-caused inactivation of CYP1A2 in a concentration-dependent manner. In conclusion, rofecoxib is a potent, metabolism-dependent inhibitor of CYP1A2, a cytochrome P450 form contributing to rofecoxib metabolism. The results provide a mechanistic explanation for the interactions of rofecoxib with CYP1A2 substrates and may partially explain its nonlinear pharmacokinetics. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
16934051 |
Backman JT, Karjalainen MJ, Neuvonen M, Laitila J, Neuvonen PJ: Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol. 2006 Sep;62(3):345-57. AIMS: Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. METHODS: In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. RESULTS: Rofecoxib increased the area under the plasma concentration-time curve (AUC (0-infinity)) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (C (max)) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t (1/2)) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC (0-25) of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). CONCLUSIONS: Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
16758262 |
Backman JT, Granfors MT, Neuvonen PJ: Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol. 2006 Jun;62(6):451-61. Epub 2006 Apr 27. OBJECTIVE: Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism. METHODS: In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases. RESULTS: Rifampicin moderately reduced the peak plasma concentration (by 51%; P = 0.002) and area under the plasma concentration-time curve [AUC (0-infinity)] (by 54%; P = 0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC (0-infinity) ratios were slightly (by 30%; P = 0.014; and by 38%; P = 0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P < 0.005), but that of M-10 was increased (P = 0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P = 0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P = 0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC (0-infinity) of tizanidine and the tizanidine/M-3 AUC (0-infinity) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin. CONCLUSIONS: Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
16198659 |
Granfors MT, Backman JT, Laitila J, Neuvonen PJ: Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther. 2005 Oct;78(4):400-11. BACKGROUND AND OBJECTIVE: Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with tizanidine. METHODS: In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg tizanidine. Plasma and urine concentrations of tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. RESULTS: The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of tizanidine was 3.9 times greater (P <.001) and the mean peak plasma tizanidine concentration (Cmax) was 3.0 times higher (P <.001) in the OC users than in the control subjects. In 1 OC user the AUC0-infinity of tizanidine exceeded the mean AUC0-infinity of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged tizanidine into urine was, on average, 3.8 times greater (P=.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P <.001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC0-infinity and peak concentration of tizanidine in plasma, with its excretion into urine, and with, for example, the tizanidine/M-3 and tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by tizanidine more in the OC users (-29+/- 10 mm Hg and -21+/- 8 mm Hg, respectively) than in the control subjects (-17+/- 9 mm Hg and -13+/- 5 mm Hg, respectively) (P < .01). CONCLUSIONS: OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when tizanidine is prescribed to OC users. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
15592331 |
Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ: Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004 Dec;76(6):598-606. BACKGROUND AND OBJECTIVE: Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. RESULTS: Ciprofloxacin increased the area under the plasma concentration-time curve from time 0 to infinity [AUC (0-infinity)] of tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (-35 mm Hg versus -15 mm Hg, P = .001), diastolic blood pressure (-24 mm Hg versus -11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC (0-infinity) of tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. CONCLUSIONS: Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
15060511 |
Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ: Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther. 2004 Apr;75(4):331-41. OBJECTIVE: Our objective was to study the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of tizanidine, a centrally acting skeletal muscle relaxant. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers took 100 mg fluvoxamine or placebo orally once daily for 4 days. On day 4, each ingested a single 4-mg dose of tizanidine. Plasma concentrations of tizanidine and fluvoxamine and pharmacodynamic variables were measured. A caffeine test was performed on day 3 to examine the role of cytochrome P450 (CYP) 1A2 in tizanidine pharmacokinetics. RESULTS: On average, fluvoxamine increased the total area under the concentration-time curve [AUC (0- infinity )] of tizanidine 33-fold (range, 14-fold to 103-fold; P =.000002) and the peak plasma concentration 12-fold (range, 5-fold to 32-fold; P =.000001). The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours (P =.00004) by fluvoxamine. The AUC (0- infinity ) of tizanidine and its increase by fluvoxamine correlated with the caffeine/paraxanthine ratio and its increase, respectively (P <.03). All pharmacodynamic variables revealed a significant difference between the fluvoxamine and placebo phases, eg, in the maximal effects on systolic blood pressure (-35 mm Hg, P =.000009), diastolic blood pressure (-20 mm Hg, P =.00002), heart rate (-4 beats/min, P =.007), Digit Symbol Substitution Test (P =.0003), subjective drug effect (P =.0000001), and drowsiness (P =.0002). In particular, the decrease in systolic blood pressure, to the level of 80 mm Hg or even less, was an alarming finding. CONCLUSIONS: Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Inhibition of tizanidine-metabolizing enzyme (s), mainly CYP1A2, by fluvoxamine seems to explain the observed interaction. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided. |
| tizanidine |
cytochrome-P450-1A2 |
True Positive |
14998432 |
Granfors MT, Backman JT, Laitila J, Neuvonen PJ: Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol. 2004 Mar;57(3):349-53. AIMS: To identify the cytochrome p450 (CYP) enzyme (s) that catalyze the metabolism of tizanidine in vitro. METHODS: The effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated. RESULTS: Incubation of tizanidine (80 nm) with human liver microsomes resulted in time- and NADPH-dependent substrate consumption with a half-life of 50 min, initial reaction velocity of 1.1 pmol x min-1 x mg-1 protein and intrinsic clearance of 17 ml x min-1 x kg-1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well-stirred and parallel-tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but other recombinant CYPs had little metabolic capacity for the drug. CONCLUSIONS: CYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo. |
| tizanidine |
prolyl-endopeptidase |
True Positive |
3330562 |
Yoshimoto T, Kado K, Matsubara F, Koriyama N, Kaneto H, Tsura D: Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect. J Pharmacobiodyn. 1987 Dec;10(12):730-5. Several peptides and peptide derivatives were tested for their inhibitory effect on prolyl endopeptidase and possible properties as anti-amnesic agents. Among the compounds tested, Z-Gly-Pro-CH2Cl, Z-Val-prolinal, Boc-Pro-prolinal, Z-Pro-prolinal, aniracetam and pramiracetam inhibited the enzyme activities at Ki values in the order of nM to microM, and the effect of the prolinal-containing peptide derivatives was specific for prolyl endopeptidase. Z-Pro-prolinal was the most effective inhibitor in vitro (Ki = 5 nM) and in vivo (50 to 70% inhibition in various organs of rat at a dose of 1 mumol/animal i.p.). Regional differences were observed in the effect of inhibitors on the brain enzyme activities: most active in mesencephalon, followed by striatum, cerebellum, hippocampus, hypothalamus; and inactive in cerebral cortex and medulla oblongata. In the passive avoidance learning test using rats, pretreatment with Z-Pro-prolinal prevented the induction of amnesia by scopolamine at the dose of 1 mumol/animal, i.p. Z-Val-prolinal, Z-Pyr-prolinal and Z-Gly-Pro-CH2Cl were also effective in the retention test at 24 and 48 h after the training trial. The antiamnesic effect of these compounds was approximately parallel to the in vitro inhibitory activities on prolyl endopeptidase. These results suggest the possibility that the inhibitors exhibit their anti-amnesic effect through the regulation of the enzyme activity in the brain. |
| tizanidine |
integrator |
False Positive |
2344648 |
Jerabek J, Krejcova H, Cerny R, Vyskocilova M: [The effect of muscle relaxants on the function of the vestibulo-ocular reflex arc]. Cesk Neurol Neurochir. 1990 Mar;53(2):83-8. Baclofen affects in experiments the reactivity of the vestibuloocular reflex by influencing the time constant of the vestibular nystagmus. The authors compare in three healthy volunteers the reactivity of the vestibular apparatus after administration of Baclofen and a new muscle-relaxant drug tizanidine. The authors evaluate basic parameters of the vestibular and optokinetic nystagmus (gain and time constant), discuss the problem of GABAergic (Baclofen) and monoaminergic (tizanide) receptors kin the area of the vestibular apparatus. As regards the effect on the reactivity of the vestibular system, tizanidine does not affect immediately the response of the vestibuloocular reflex but interferes with processes ensured by the central neuronal integrator. |
| tizanidine |
substance-P |
False Positive |
1717870 |
Ono H, Mishima A, Ono S, Fukuda H, Vasko MR: Inhibitory effects of clonidine and tizanidine on release of substance P from slices of rat spinal cord and antagonism by alpha-adrenergic receptor antagonists. Neuropharmacology. 1991 Jun;30(6):585-9. Effects of clonidine and tizanidine, which have antinociceptive and alpha 2-agonistic actions, were studied on the release of substance P from slices of spinal cord from the rat. Veratridine-evoked depolarization induced a 2-3-fold increase in the release of substance P from the slices of spinal cord. Exposure of the cord tissue to 10 microM clonidine and tizanidine significantly reduced the release of substance P. The inhibitory effects of clonidine and tizanidine were attenuated by pre-exposure of the tissue to 10 microM piperoxane, which has alpha 2-antagonistic activity and the inhibitory effect of clonidine was attenuated by 10 microM yohimbine. Moreover, the inhibitory effects of clonidine and tizanidine were also blocked by a small dose of prazosin, an antagonist for alpha 1- and alpha 2B-receptors. None of the antagonists had any effect on release of substance P, when given alone. These results suggest that alpha 2B-adrenoceptors are involved in the inhibitory effects of clonidine and tizanidine on the release of substance P. |
| tizanidine |
growth-hormone |
True Positive |
8615503 |
Miettinen TJ, Kanto JH, Salonen MA, Scheinin M: The sedative and sympatholytic effects of oral tizanidine in healthy volunteers. Anesth Analg. 1996 Apr;82(4):817-20. Tizanidine, an imidazoline derivative with alpha 2-receptor-mediated central muscle relaxant activity, is in widespread clinical use for the treatment of spasticity. To evaluate its possible role in anesthesia we assessed the sedative and sympatholytic effects of orally administered tizanidine in a double-blind, placebo-controlled, randomized, cross-over study in six healthy male volunteers. Three different doses of tizanidine (4, 8, and 12 mg) were tested and compared to clonidine 150 micrograms. The sedative and sympatholytic effects of tizanidine 12 mg were comparable in magnitude to those of clonidine 150 micrograms, but the effects of clonidine were longer lasting. Similarly, the observed decreases in arterial blood pressure (diastolic, 13% and 19%; systolic, 10% and 8% for tizanidine and clonidine, respectively) and salivation were comparable in magnitude but of shorter duration after tizanidine 12 mg than after clonidine. Clonidine and tizanidine 12 mg had also similar effects on the secretion of growth hormone. Our results indicate that the effects of a single 12-mg oral dose of tizanidine resemble those of 150 micrograms oral clonidine, but are of shorter duration. Tizanidine may thus be a useful alternative to clonidine as an orally active, short-acting alpha 2-adrenoceptor agonist in the perioperative period. |
| quinidine |
5-HT-6 |
False Positive |
8825350 |
del Pozo BF, Perez-Vizcaino F, Villamor E, Zaragoza F, Tamargo J: Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta. Br J Pharmacol. 1996 Jan;117(1):105-10. 1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10 (-6) M-3 x 10 (-4) M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca (2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10 (-4) M) and quinine (< 3 x 10 (-4) M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10 (-5) M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10 (-4) M) inhibited to a similar extent both the phasic (induced in Ca (2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner. |
| quinidine |
OCT1 |
True Positive |
10455332 |
Dautrey S, Felice K, Petiet A, Lacour B, Carbon C, Farinotti R: Active intestinal elimination of ciprofloxacin in rats: modulation by different substrates. Br J Pharmacol. 1999 Aug;127(7):1728-34. 1. Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net intestinal elimination of ciprofloxacin: an open-intestinal perfusion model and an intestinal loop model respectively. 2. In the presence of quinidine, verapamil and cyclosporin (substrates of the P-glycoprotein (P-gp)), plasma AUCs of ciprofloxacin were 1.5 - 2 fold increased, while biliary clearance (1.5 - 2 fold), intestinal overall and net clearances (2 - 4 fold and 1.5 - 8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P-gp, as the OCT1 transporter which could be inhibited by quinidine. 3. With cephalexin and azlocillin, two beta-lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and intestinal overall clearances decreased in a similar fashion (1.3 - 2 fold), suggesting the involvement of organic anion and/or cation transporters. 4. In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on intestinal clearance of ciprofloxacin. In contrast, with pefloxacin, overall intestinal clearance of ciprofloxacin was decreased and net intestinal clearance increased. 5. The specificity of ciprofloxacin intestinal transport appears to be different from P-gp as outlined by the lack of competition with sparfloxacin, a P-gp substrate. Ciprofloxacin intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil. |
| quinidine |
OCT1 |
True Positive |
10215651 |
Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M, Sai Y, Tsuji A: Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999 May;289(2):768-73. In the present study, functional characteristics of organic cation transporter (OCTN) 1, which was cloned as the pH-dependent tetraethylammonium (TEA) transporter when expressed in mammalian human embryonic kidney (HEK) 293 cells, were further investigated using Xenopus oocytes as well as HEK293 cells as gene expression systems. When OCTN1-derived complementary RNA was injected into Xenopus oocytes, pH-dependent transport of [14C] TEA was observed as the same in HEK293 cells. In contrast, a replacement of sodium ions with potassium ions in the surrounding medium did not cause any change in [14C] TEA uptake in Xenopus oocytes expressed with OCTN1. In addition, when OCTN1 was expressed in HEK293 cells, efflux of TEA from the cells was pH dependent, with an accelerated rate at acidic external medium pH. Accordingly, membrane potential or sodium ions are suggested to have no influence on [14C] TEA transport and the transport activity of OCTN1 is directly affected by pH itself. Furthermore, addition of the unlabeled TEA in external medium enhanced the efflux of preloaded [14C] TEA. These observations suggest that OCTN1 is a pH-dependent and bidirectional TEA transporter. OCTN1-mediated [14C] TEA uptake was inhibited by various organic cations such as cimetidine, procainamide, pyrilamine, quinidine, quinine, and verapamil. In addition, uptakes of cationic compounds such as [3H] pyrilamine, [3H] quinidine, and [3H] verapamil and zwitterionic L-[3H] carnitine were increased by expression of OCTN1 in Xenopus oocytes. Accordingly, OCTN1 was functionally demonstrated to be a multispecific and pH-dependent organic cation transporter, which presumably functions as a proton/organic cation antiporter at the renal apical membrane and other tissues. |
| quinidine |
OCT1 |
True Positive |
9808712 |
Urakami Y, Okuda M, Masuda S, Saito H, Inui KI: Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther. 1998 Nov;287(2):800-5. We have isolated a kidney-specific organic cation transporter, rat OCT2, which is distinct from rat OCT1 (Okuda M, Saito H, Urakami Y, Takano M and Inui K (1996) Biochem Biophys Res Commun 224:500-507). In our study, the functional characteristics and membrane localization of OCT1 and OCT2 were investigated by uptake studies using MDCK cells transfected with rat OCT1 or OCT2 cDNA (MDCK-OCT1 or MDCK-OCT2) and immunological studies. Tetraethylammonium (TEA) uptake by both MDCK-OCT1 and MDCK-OCT2 cells was markedly elevated when TEA was added to the basolateral medium, but not to the apical medium. Efflux of TEA from MDCK-OCT1 and MDCK-OCT2 cells was not changed by extracellular pH from 5.4 to 8.4, whereas TEA uptake by both transfectants was decreased by acidification of extracellular medium. Apparent Km values for TEA uptake by MDCK-OCT1 and MDCK-OCT2 cells were 38 and 45 microM, respectively. Although various hydrophilic organic cations such as 1-methyl-4-phenylpyridinium, cimetidine, quinidine, nicotine, N1-methylnicotinamide and guanidine markedly inhibited TEA uptake by both MDCK-OCT1 and MDCK-OCT2 cells, there were no significant differences in the apparent inhibition constants (Ki) against these organic cations between both transfectants. Furthermore, immunological studies using a polyclonal antibody against OCT1 revealed that OCT1 was expressed in the basolateral membranes but not in the brush-border membranes of the rat kidney. These results suggested that both OCT1 and OCT2 are basolateral-type organic cation transporters with broad substrate specificities, mediating tubular secretion of cationic drugs. |
| quinidine |
hOCT1 |
True Positive |
11408531 |
van Montfoort JE, Muller M, Groothuis GM, Meijer DK, Koepsell H, Meier PJ: Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5. Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small "type I" (system1) and for bulky "type II" (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation uptake, we compared the organic cation transport properties of the rat and human organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-transporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injected Xenopus laevis oocytes. Based on characteristic cis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was inhibited by the OATP-A substrate N-methyl-quinidine. The latter substrate was also transported by rOCT1 and hOCT1, demonstrating distinct organic cation transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate that unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charge for carrier-mediated uptake into hepatocytes. In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based type I and II organic cation transporter classification cannot be extended without modification from rat to human. |
| quinidine |
CYP2E1 |
False Positive |
12814958 |
Kobayashi K, Urashima K, Shimada N, Chiba K: Selectivities of human cytochrome P450 inhibitors toward rat P450 isoforms: study with cDNA-expressed systems of the rat. Drug Metab Dispos. 2003 Jul;31(7):833-6. The aim of this study was to determine the selectivities of chemical inhibitors for human cytochrome P450 (P450) isoforms toward the corresponding rat P450 isoforms by using cDNA-expressed rat P450s (CYP1A2, CYP2A1, CYP2C6, CYP2C11, CYP2D2, CYP2E1, CYP3A1, and CYP3A2). Among the inhibitor probes for human P450s used in this study, only sulfaphenazole showed a selective inhibitory effect on the activity of the corresponding rat P450 isoform (CYP2C6). Furafylline also preferentially inhibited the activity of rat CYP1A2. However, methoxalen and ketoconazole more strongly inhibited the activities of other P450 isoforms than those of the corresponding rat P450 isoforms, CYP2A1 and CYP3A1/2, respectively. On the other hand, quinidine and aniline had little effect on the activities of the corresponding rat P450 isoforms, CYP2D2, and rat CYP2E1, respectively. These results suggest that chemical probes that have been used for human P450 isoforms do not always exhibit the same selectivity for the corresponding rat P450 isoforms. However, it appears that sulfaphenazole can be used as a selective inhibitor for rat CYP2C6. In addition, furafylline may also be a relatively selective inhibitor for rat CYP1A2. |
| quinidine |
CYP2E1 |
False Positive |
10594487 |
Damkier P, Hansen LL, Brosen K: Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol. 1999 Dec;48(6):829-38. AIMS: In vitro studies suggest that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine. METHODS: An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied. RESULTS: Concomitant administration of diclofenac reduced the partial clearance of quinidine by N-oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram did not alter any of the pharmacokinetic parameters of quinidine. Concomitant administration of itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxylation and partial clearance by N-oxidation by 61, 84 and 73%, respectively. The renal clearance was reduced by 60% and the elimination half-life increased by 35%. Concomitant administration of grapefruit juice reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 15, 19 and 27%, respectively. The elimination half-life of quinidine was increased by 19%. The caffeine metabolic index was reduced by 25%. Concomitant administration of erythromycin reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 34, 50 and 33%, respectively. Cmax was increased by 39%. CONCLUSIONS: The results confirm an important role for CYP3A4 in the oxidation of quinidine in vivo, and this applies particularly to the formation of 3-hydroxyquinidine. While a minor contribution of CYP2C9 to the N-oxidation of quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzymes in the oxidation of quinidine in vivo is unlikely. |
| quinidine |
KCR1 |
True Positive |
14525949 |
Kupershmidt S, Yang IC, Hayashi K, Wei J, Chanthaphaychith S, Petersen CI, Johns DC, George AL Jr, Roden DM, Balser JR: The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines. FASEB J. 2003 Dec;17(15):2263-5. Epub 2003 Oct 2. The cardiac potassium channel encoded by the human ether-a-go-go related gene (HERG) is blocked by a diverse array of common therapeutic compounds. Even transient exposure to such agents may provoke the life-threatening cardiac arrhythmia torsades de pointes in some, but not all, individuals. Although the molecular and genetic factors predicting such wide variability in drug response remain unclear, known sequence variations within the coding region of HERG do not explain the adverse drug response in many cases. Although other proteins can modulate HERG function, no studies have identified protein partners capable of limiting the pharmacological sensitivity of HERG. Here we show that KCR1, a protein identified previously in rat cerebellum, is a plasma membrane-associated protein expressed at the RNA level in the human heart and can be immunoprecipitated with HERG. Functionally, KCR1 reduces the sensitivity of HERG to classic proarrhythmic HERG blockers (sotalol, quinidine, dofetilide) in both cardiac and noncardiac cell lines. We propose that KCR1, when coupled to HERG, may limit the sensitivity of HERG to proarrhythmic drug blockade and may be a rational target for modifying the proarrhythmic effects of otherwise clinically useful compounds. |
| quinidine |
EAG1 |
True Positive |
11943152 |
Schonherr R, Gessner G, Lober K, Heinemann SH: Functional distinction of human EAG1 and EAG2 potassium channels. FEBS Lett. 2002 Mar 13;514(2-3):204-8. Human ether a go-go potassium channel 2 (hEAG2) was cloned and its properties were compared with the previously characterized isoform hEAG1. In the Xenopus oocyte expression system the time course of activation was about four times slower and the voltage required for half-maximal subunit activation was about 10 mV greater for hEAG2 channels. However, its voltage dependence was smaller and, therefore, hEAG2 channels start to open at more negative voltages than hEAG1. Coexpression of both isoforms and kinetic analysis of the resulting currents indicated that they can form heteromeric channel complexes in which the slow activation phenotype of hEAG2 is dominant. Upon expression in mammalian cells, quinidine blocked hEAG1 channels (IC (50) 1.4 microM) more potently than hEAG2 channels (IC (50) 152 microM), thus providing a useful tool for the functional distinction between hEAG1 and hEAG2 potassium channels. |
| quinidine |
CYP2A6 |
False Positive |
16035375 |
Fuhr U, Kober S, Zaigler M, Mutschler E, Spahn-Langguth H: Rate-limiting biotransformation of triamterene is mediated by CYP1A2. . Int J Clin Pharmacol Ther. 2005 Jul;43(7):327-34. OBJECTIVE: Triamterene (TA), a potassium-sparing diuretic, is extensively metabolized by hydroxylation in 4'-position and subsequent conjugation by cytosolic sulfotransferases. To identify the cytochrome P450 enzyme (s) catalyzing hydroxylation of triamterene (the rate-limiting step in the formation of the sulfate ester (STA)), in vitro incubation studies were performed with human liver microsomes. METHODS: Initial rates of TA hydroxylation (0 - 300 microM) were determined during a ten-minute-incubation period with liver microsomes of two donors. The role of individual CYP enzymes was determined by pre-incubation with selective inhibitors/alternative substrates. Vice versa, the effect of TA (0 - 500 microM) on 3-demethylation of caffeine (0 - 1,000 microM) was assessed. Metabolite concentrations were estimated by reversed-phase HPLC methods. RESULTS: TA Km values without inhibitors were 60 and 142 microM, Vmax was 177 and 220 pmol/min/mg protein, respectively. Mean inhibitor induced changes of 4'-hydroxy-TA formation were as follows: Furafylline 25 microM (CYP1A2), complete inhibition (-100%); omeprazole 250 microM (CYP1A2 inhibitor/CYP2C 19 substrate), -30%; coumarin 25 microM (CYP2A6), -11%; quinidine 25 microM (CYP2D6), -9%; ketoconazole 25 microM (CYP3A), -18%; and erythromycin 250 microM (CYP3A), -8%. In the reverse inhibition studies, TA competitively inhibited caffeine 3-demethylation with Ki values of 65 and 111 microM, respectively. CONCLUSION: 4'-hydroxylation of TA in humans appears to be mediated exclusively by CYP1A2. Inhibition or induction of CYP1A2 will change the time course of both TA and its active phase-II metabolite. The net pharmacodynamic effect of such changes is difficult to predict and needs to be evaluated in clinical studies. |
| quinidine |
CYP2A6 |
False Positive |
8591727 |
Pichard L, Gillet G, Bonfils C, Domergue J, Thenot JP, Maurel P: Oxidative metabolism of zolpidem by human liver cytochrome P450S. Drug Metab Dispos. 1995 Nov;23(11):1253-62. The aim of this study was to identify the form (s) of cytochrome P450 (CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represents the main way of metabolism in humans. In human liver microsomes, zolpidem was converted to alcohol derivatives. Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities. Liver microsomes from CYP2D6-deficient patients exhibited normal activity. Production of alcohol derivatives was significantly inhibited by anti-CYP3A antibodies and by ketoconazole. Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, CYP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (including propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, aniline, and lauric acid) produced a moderate or no inhibitory effect. cDNA-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in similar amounts. In human hepatocytes in primary culture, zolpidem was extensively and almost exclusively converted to one of the carboxylic acid derivatives, the main species identified in vivo. Treatment of cells with inducers of CYP1A (beta-naphthoflavone) and CYP3A (rifampicin and phenobarbital) greatly increased the rate of production of this metabolite. We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4. Both CYP1A2 and CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor. |
| quinidine |
sodium-channel |
True Positive |
9330843 |
Kolecki PF, Curry SC: Poisoning by sodium channel blocking agents. Crit Care Clin. 1997 Oct;13(4):829-48. Poisoning by drugs that block voltage-gated sodium channels produces intraventricular conduction defects, myocardial depression, bradycardia, and ventricular arrhythmias. Human and animal reports suggest that hypertonic sodium bicarbonate may be effective therapy for numerous agents possessing sodium channel blocking properties, including cocaine, quinidine, procainamide, flecainide, mexiletine, bupivacaine, and others. |
| quinidine |
sodium-channel |
True Positive |
8911721 |
Wyse KR, Bursill JA, Campbell TJ: Differential effects of antiarrhythmic agents on post-pause repolarization in cardiac Purkinje fibres. Clin Exp Pharmacol Physiol. 1996 Sep;23(9):825-9. 1. Marked action potential duration (APD) prolongation with agents such quinidine is often a precursor of early after-depolarizations and triggered activity, thought to be underlying mechanism of torsade de pointes. Episodes of torsade de pointes commonly occur following a pause. 2. We recently demonstrated that quinidine, but not disopyramide, produced marked further prolongation of APD immediately following pauses of 2-10s interpolated into a basic drive train in canine Purkinje fibres. 3. We report here experiments aimed at further elucidating the mechanisms of this phenomenon. 4. We used standard microelectrode techniques to record action potentials from canine Purkinje fibres driven at a baseline interstimulus interval (ISI) of 1000 ms. 5. We were able to reproduce the phenomenon of post-pause prolongation of APD with amitriptyline, which blocks both sodium and potassium channels, as does quinidine. Furthermore, we showed that the kinetics of interaction of amitriptyline, with the sodium channel, are similar to those known to exist for quinidine (time constant of recovery from blockade 2.3 +/- 0.6s). 6. In contrast, we were unable to reproduce post-pause prolongation of APD with three pure class III antiarrhythmic agents, D-sotalol, clofilium and dofetilide. 7. We propose that quinidine and amitriptyline behave similarly, in that they both produce two separate, opposing effects on APD. During a pause, the sodium channel-blocking action of these compounds diminishes exponentially, allowing the potassium channel blocking effect to become manifest as post-pause prolongation of APD. None of D-sotalol, clofilium or dofetilide exhibits significant sodium channel blockade and, thus, these agents do not manifest post-pause prolongation of repolarization. Disopyramide does produce sodium channel blockade, but recovery from this effect is much slower than for quinidine or amitriptyline (time constant 12-50s). Thus, we propose insufficient recovery occurs during the intervals under study to uncover the action potential-prolonging effect of the unopposed potassium channel blockade for disopyramide. |
| quinidine |
sodium-channel |
True Positive |
7995008 |
Wang L, Sheldon RS, Mitchell LB, Wyse DG, Gillis AM, Chiamvimonvat N, Duff HJ: Amiloride-quinidine interaction: adverse outcomes. Clin Pharmacol Ther. 1994 Dec;56(6 Pt 1):659-67. OBJECTIVES: Previous studies have reported beneficial antiarrhythmic effects when selected drugs were combined. The purpose of this study was to assess whether a favorable interaction would occur with amiloride and quinidine. DESIGN: The antiarrhythmic and electrophysiologic effects of quinidine alone and in combination with amiloride were assessed in 10 patients with inducible sustained ventricular tachycardia. Parallel electrophysiologic studies assessed this drug combination in guinea pig papillary muscle. RESULTS: None of the patients had adverse effects during quinidine monotherapy. However, seven of 10 patients had adverse responses to the combination treatment: three patients had suppression of inducible ventricular tachycardia during quinidine monotherapy but had sustained ventricular tachycardia induced during combination treatment; three other patients had somatic side effects that resulted in discontinuation of the combination therapy but were absent during quinidine monotherapy; and one patient had 12 episodes of sustained ventricular tachycardia during this combination therapy. The patient had no such response during monotherapy. Surface QRS duration was significantly more prolonged during combination therapy than during monotherapy. Parallel electrophysiologic effects assessed this drug combination in guinea pig papillary muscle. The combination of amiloride (1 mumol/L) and quinidine (10 mumol/L) synergistically decreased the maximum rate of rise of phase 0 of the action potential (Vmax) (43 +/- 12 V/sec) compared with quinidine alone (24 +/- 9 V/sec) because of a greater degree of tonic block of Vmax (14% +/- 6%) as compared to quinidine alone (3% +/- 3%) with no significant change in action potential duration. CONCLUSIONS: Amiloride exaggerates the effects of quinidine on QRS duration in patients and on Vmax during in vitro study, which implies that the proarrhythmic effect of the combination of amiloride and quinidine may be associated with synergistic increase in sodium channel blockade. |
| quinidine |
sodium-channel |
True Positive |
7791114 |
Takeo S, Tanonaka K, Hayashi M, Yamamoto K, Liu JX, Kamiyama T, Yamaguchi N, Miura A, Natsukawa T: A possible involvement of sodium channel blockade of class-I-type antiarrhythmic agents in postischemic contractile recovery of isolated, perfused hearts. J Pharmacol Exp Ther. 1995 Jun;273(3):1403-9. The present study was undertaken to test the hypothesis that the degree of sodium channel blockade by class-I-type antiarrhythmic agents accounts for enhancement of postischemic contractile recovery of ischemic/reperfused hearts. Electrophysiological studies showed that the class-I-type antiarrhythmic agents quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide and pilsicainide suppressed the Vmax value of the rat left ventricular muscle cell, a marker of sodium channel blockade, in a concentration-dependent manner. Isolated rat hearts were subjected to 35 min of ischemia and 60 min of reperfusion. Postischemic contractile recovery, which was never detected in untreated hearts, was enhanced in hearts pretreated with these antiarrhythmic agents during the last 3 min before ischemia at concentrations ranging from 3 to 300 microM. Tissue Na, but not Ca, accumulation was also detected in the ischemic heart, and tissue Na and Ca accumulation was observed in the reperfused heart, which suggests that sodium overload occurs during ischemia, followed by sodium and calcium overload during reperfusion. The degree of postischemic contractile recovery seen in the presence of these antiarrhythmic agents was inversely related to tissue Na or Ca accumulation after reperfusion, which suggests that class-I-type antiarrhythmic agents inhibit sodium overload occurring in ischemic/reperfused myocardial cells. A close relationship between postischemic contractile recovery of the perfused heart and depression in the Vmax value of the ventricular muscle was also observed. These results suggest that the ability class-I-type antiarrhythmic agents to inhibit myocardial sodium channels plays a significant role in the enhancement of postischemic contractile recovery of the ischemic/reperfused heart. |
| quinidine |
epidermal-growth-factor-receptor |
False Positive |
11691539 |
Tahara S, Fukuda K, Kodama H, Kato T, Miyoshi S, Ogawa S: Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes. J Am Coll Cardiol. 2001 Nov 1;38(5):1554-63. OBJECTIVES: We sought to determine whether potassium (K (+)) channel blockers (KBs) can activate extracellular signal-regulated kinase (ERK) and to characterize the upstream signals leading to ERK activation in cardiomyocytes. BACKGROUND: Because KBs attenuate K (+) outward current, they may possibly prolong the duration of action potentials, leading to an increase in calcium (Ca (2+)) transient ([Ca (2+)](i)) in cardiomyocytes. Elevation of intracellular Ca (2+) levels can trigger various signaling events. Influx of Ca (2+) through L-type Ca (2+) channels after membrane depolarization induced activation of MEK and ERK through activation of Ras in neurons. Although KBs are frequently used to treat cardiac arrhythmias, their effect on signaling pathways remains unknown. METHODS: Primary cultured rat cardiomyocytes were stimulated with four different KBs-4-aminopyridine (4-AP), E-4031, tetra-ethylammonium and quinidine-and phosphorylation of ERK, proline-rich tyrosine kinase 2 (Pyk2) and epidermal growth factor receptor (EGFR) was detected. Action potentials were recorded by use of a conventional microelectrode. (Ca (2+))(i) was monitored by the fluorescent calcium indicator Fluo-4. RESULTS: E-4031, 4-AP, tetra-ethylammonium and quinidine induced phosphorylation of ERK. 4-Aminopyridine prolonged the duration of action potentials by 37% and increased (Ca (2+))(i) by 52% at 1 mmol/l. Pre-incubation of ethyleneglycoltetraacetic acid, 1,2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis and diltiazem completely blocked this phosphorylation, whereas flufenamic acid and benzamil did not. 4-Aminopyridine induced tyrosine phosphorylation of Pyk2 and EGFR, which peaked at 5 and 10 min, respectively. Cytochalasin D, AG1478 and dominant-negative EGFR strongly inhibited the phosphorylation of ERK, whereas calphostin C, calmidazolium and KN62 did not. CONCLUSIONS: These findings indicate that KBs induce ERK activation, which starts with Ca (2+) entry through the L-type Ca (2+) channel in cardiomyocytes, and that EGFR and Pyk2 are involved in this activation. |
| quinidine |
N-methyl-D-aspartate-receptor |
True Positive |
7617305 |
Jolivalt C, Minn A, Vincent-Viry M, Galteau MM, Siest G: Dextromethorphan O-demethylase activity in rat brain microsomes. Neurosci Lett. 1995 Feb 24;187(1):65-8. CYP2D, a genetically variable isoform of cytochrome P450, has been characterized mainly in the liver and the brain of mammals by measurement of debrisoquine hydroxylase activity. Moreover, 'poor debrisoquine metabolizer' phenotype is significantly increased in Parkinson's disease patients. We present here the first demonstration that the activity of the CYP2D isoform can be characterized in rat brain microsomes by the measurement of dextromethorphan O-demethylase capacity. The cerebral formation of dextrorphan, an antagonist of the N-methyl-D-aspartate receptor, was inhibited by the presence of quinidine and N-methyl-4-phenylpyridinium (MPP+), a dopaminergic neurotoxin inducing a chemical parkinsonism in humans. |
| quinidine |
tumor-necrosis-factor-alpha |
True Positive |
9315521 |
Matsumori A, Ono K, Nishio R, Nose Y, Sasayama S: Amiodarone inhibits production of tumor necrosis factor-alpha by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation. 1997 Sep 2;96(5):1386-9. BACKGROUND: Recent studies suggest that cytokines such as tumor necrosis factor (TNF)-alpha and interleukins (ILs) are capable of modulating cardiovascular function and that drugs used in the treatment of heart failure have various modulatory effects on the production of cytokines. This study was performed to examine the effects of amiodarone (a drug shown to be beneficial in some patients suffering from heart failure) versus other antiarrhythmic agents on the production of cytokines in vitro. METHODS AND RESULTS: Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured with 0.1, 1, and 10 micromol/L of amiodarone, quinidine, disopyramide, and lidocaine in the presence of lipopolysaccharide. After 24 hours' incubation, TNF-alpha, IL-1beta, and IL-6 were measured in the culture supernatants by an enzyme-linked immunosorbent assay. TNF-alpha production was inhibited by amiodarone but stimulated by quinidine in a concentration-dependent manner. Disopyramide and lidocaine tended to increase TNF-alpha production. IL-6 production was decreased by amiodarone in all concentrations but was increased significantly by disopyramide. Modulation of IL-1beta production by amiodarone was biphasic and significantly increased at a concentration of 10 micromol/L. CONCLUSIONS: These previously unrecognized immunomodulatory effects of amiodarone may contribute to its beneficial effects in heart failure patients. |
| quinidine |
alpha-1-acid-glycoprotein |
True Positive |
11814462 |
Li JH, Xu JQ, Cao XM, Ni L, Li Y, Zhuang YY, Gong JB: Influence of the ORM1 phenotypes on serum unbound concentration and protein binding of quinidine. Clin Chim Acta. 2002 Mar;317(1-2):85-92. BACKGROUND: Only unbound or free drug in plasma can be transported to its site of action. The fraction of unbound drug in plasma varies widely for highly bound drugs among individuals. The genetic polymorphism of orosomucoid (ORM) could be related to the interindividual variability in plasma binding of basic drugs, as ORM is the transport protein for these drugs in plasma. The ORM is a major binding protein in plasma for various basic drugs and is coded by two loci, ORM1 and ORM2, which are closely linked on chromosome 9q31--> 34.1. ORM1 locus is highly polymorphic and the ORM2 locus is monomorphic in most population. METHODS: Twenty-eight healthy volunteers were selected with three ORM1 phenotypes, containing homozygotes ORM1 F1 (n=10) and ORM1 S (n=8), and heterozygote ORM1 F1S (n=10), identified by isoelectric focusing on polyacrylamide gels followed immunoblotting after desialylation of sera. After a single oral dose of quinidine 200 mg, serum total (HPLC) and unbound concentrations in ultrafiltrate (ultrafiltration/HPLC) were determined, and the pharmacokinetic parameters and protein binding rate were calculated. RESULTS: Serum concentrations of ORM (553.8-573.2 mg/l) and albumin proteins (57.5-58.4 mg/l) were similar in the three groups (P> 0.05). Unbound quinidine concentration in ORM1 F1 phenotype subjects was higher than that in ORM1 S and ORM1 F1S phenotype; the free drug percentage for the subjects with ORM1 F1 phenotype (19.79%) was twice as high as that with ORM1 S phenotype (10.96%) (P <0.01) at 24 h after administration of oral quinidine when the state of disposition equilibrium occurred. The elimination t (1/2) values and the other pharmacokinetic parameters of quinidine were not affected by the different ORM1 phenotypes. CONCLUSIONS: Different ORM1 phenotypes may affect the disposition of quinidine, a basic drug, rather than its hepatic metabolism and elimination. The functional heterogeneity of ORM1 could be responsible for the differences in plasma binding of quinidine. Therefore, monitoring of the unbound quinidine concentration would be important for the patients with different ORM1 phenotypes who are treated with quinidine. |
| quinidine |
alpha-1-acid-glycoprotein |
True Positive |
9620113 |
McCollam PL, Crouch MA, Arnaud P: Caucasian versus African-American differences in orosomucoid: potential implications for therapy. Pharmacotherapy. 1998 May-Jun;18(3):620-6. We conducted a prospective, nonrandomized study in healthy volunteers to determine if racial differences exist in orosomucoid (ORM) and its variants, and to examine quinidine and lidocaine binding to the protein. Total ORM serum concentrations were measured by Laurell-Rocket immunoelectrophoresis. Allele types were determined by isoelectric focusing and immunoblotting. Total and unbound quinidine and lidocaine concentrations were measured with standard fluorescence polarization immunoassays after ultrafiltration. The frequency of the common ORM alleles was similar between 38 Caucasians and 67 African-Americans. Mean total ORM concentration was significantly lower in Caucasians (57.3 +/- 25.4 vs 73.2 +/- 33.9 mg/dl, p=0.01). However, more Caucasians took oral contraceptives, which may have decreased ORM concentrations. Quinidine unbound fraction (UF) was related to ORM phenotype. The highest UF was found with ORM 1-S (p=0.009). There were no significant relationships between ORM phenotype and lidocaine UF. Overall, African-Americans had higher ORM concentrations than Caucasians. Quinidine binding showed significant relationships to specific ORM variants. |
| quinidine |
OATP |
True Positive |
11408531 |
van Montfoort JE, Muller M, Groothuis GM, Meijer DK, Koepsell H, Meier PJ: Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5. Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small "type I" (system1) and for bulky "type II" (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation uptake, we compared the organic cation transport properties of the rat and human organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-transporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injected Xenopus laevis oocytes. Based on characteristic cis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was inhibited by the OATP-A substrate N-methyl-quinidine. The latter substrate was also transported by rOCT1 and hOCT1, demonstrating distinct organic cation transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate that unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charge for carrier-mediated uptake into hepatocytes. In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based type I and II organic cation transporter classification cannot be extended without modification from rat to human. |
| quinidine |
histone-deacetylase-1 |
True Positive |
10938272 |
Zhou Q, Melkoumian ZK, Lucktong A, Moniwa M, Davie JR, Strobl JS: Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. J Biol Chem. 2000 Nov 10;275(45):35256-63. Quinidine inhibits proliferation and promotes cellular differentiation in human breast tumor epithelial cells. Previously we showed quinidine arrested MCF-7 cells in G (1) phase of the cell cycle and led to a G (1) to G (0) transition followed by apoptotic cell death. The present experiments demonstrated that MCF-7, MCF-7ras, T47D, MDA-MB-231, and MDA-MB-435 cells transiently differentiate before undergoing apoptosis in response to quinidine. The cells accumulated lipid droplets, and the cytokeratin 18 cytoskeleton was reorganized. Hyperacetylated histone H4 appeared within 2 h of the addition of quinidine to the medium, and levels were maximal by 24 h. Quinidine-treated MCF-7 cells showed elevated p21 (WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin. Quinidine did not show evidence for direct inhibition of histone deacetylase enzymatic activity in vitro. HDAC1 was undetectable in MCF-7 cells 30 min after addition of quinidine to the growth medium. The proteasome inhibitors MG-132 and lactacystin completely protected HDAC1 from the action of quinidine. We conclude that quinidine is a breast tumor cell differentiating agent that causes the loss of HDAC1 via a proteasomal sensitive mechanism. |
| quinidine |
OCTN2 |
True Positive |
16652335 |
Amat di San Filippo C, Pasquali M, Longo N: Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Primary carnitine deficiency is a recessive disorder caused by heterogeneous mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter. Here we extend mutational analysis to eight new families with this disorder. To determine the mechanism by which missense mutations impaired carnitine transport, the OCTN2 transporter was tagged with the green fluorescent protein and expressed in CHO cells. Analysis by confocal microscopy indicated that several missense mutants (M1I, R169W, T232 M, G242 V, S280F, R282Q, W283R, A301D, W351R, R399Q, T440 M, E452 K, and T468R) matured normally to the plasma membrane. By contrast, other mutations (including R19P, DeltaF22, R83L, S280F, P398L, Y447C, and A142S/R488 H) caused significant retention of the mutant OCTN2 transporter in the cytoplasm. Failed maturation to the plasma membrane is a common mechanism in disorders affecting membrane transporters/ion channels, including cystic fibrosis. To correct this defect, we tested whether drugs reducing the efficiency of protein degradation in the endoplasmic reticulum (ER) (phenylbutyrate, curcumin) or capable of binding the OCTN2 carnitine transporter (verapamil, quinidine) could improve carnitine transport. Prolonged incubation with phenylbutyrate, quinidine, and verapamil partially stimulated carnitine transport, while curcumin was ineffective. These results indicate that OCTN2 mutations can affect carnitine transport by impairing maturation of transporters to the plasma membrane. Pharmacological therapy can be effective in partially restoring activity of mutant transporters. |
| quinidine |
NPPB |
False Positive |
17365275 |
Suzuki T, Zaima C, Moriki Y, Fukami T, Tomono K: P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood-brain barrier. J Drug Target. 2007 Jan;15(1):67-74. The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood-brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [3H] BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [3H] BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [3H] BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 x 10- 2 min- 1) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [3H] BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part. |
| quinidine |
NPPB |
False Positive |
9775982 |
Kamleiter M, Hanemann CO, Kluwe L, Rosenbaum C, Wosch S, Mautner VF, Muller HW, Grafe P: Voltage-dependent membrane currents of cultured human neurofibromatosis type 2 Schwann cells. Glia. 1998 Nov;24(3):313-22. Previous experimental observations indicate that inhibition of voltage-dependent K+ currents suppresses proliferation of normal Schwann cells. In the present study we tested the opposite relationship, i.e., whether Schwann cells from tumors with abnormally high rates of proliferation would have an increase in membrane K+ currents. Whole-cell membrane currents were studied in cultured cells from schwannomas of two neurofibromatosis type 2 (NF2) patients (n = 53), one patient with a sporadic schwannoma (n = 22), and two control subjects (n = 41). Five different types of voltage-dependent membrane currents were found in all of the Schwann cells tested. Membrane depolarization activated outward K+ and Cl- currents; quinidine was found to block the K+ current (IC50 approximately 1 microM), and NPPB reduced the Cl- current. Ba2+-sensitive inward rectifier K+ currents, fast Na+ currents, and a transient, inactivating K+ current were less frequently observed. On average, NF2 cells were found to have statistically significant higher membrane potential and larger non-inactivating K+ outward current as compared to controls. Electrophysiological parameters of Schwann cells from a sporadic schwannoma showed a tendency for larger outward currents; however, the difference did not reach statistical significance. Together the data support the suggestion of a possible link between K+ outward current and proliferation of Schwann cells. |
| quinidine |
Pyk2 |
True Positive |
11691539 |
Tahara S, Fukuda K, Kodama H, Kato T, Miyoshi S, Ogawa S: Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes. J Am Coll Cardiol. 2001 Nov 1;38(5):1554-63. OBJECTIVES: We sought to determine whether potassium (K (+)) channel blockers (KBs) can activate extracellular signal-regulated kinase (ERK) and to characterize the upstream signals leading to ERK activation in cardiomyocytes. BACKGROUND: Because KBs attenuate K (+) outward current, they may possibly prolong the duration of action potentials, leading to an increase in calcium (Ca (2+)) transient ([Ca (2+)](i)) in cardiomyocytes. Elevation of intracellular Ca (2+) levels can trigger various signaling events. Influx of Ca (2+) through L-type Ca (2+) channels after membrane depolarization induced activation of MEK and ERK through activation of Ras in neurons. Although KBs are frequently used to treat cardiac arrhythmias, their effect on signaling pathways remains unknown. METHODS: Primary cultured rat cardiomyocytes were stimulated with four different KBs-4-aminopyridine (4-AP), E-4031, tetra-ethylammonium and quinidine-and phosphorylation of ERK, proline-rich tyrosine kinase 2 (Pyk2) and epidermal growth factor receptor (EGFR) was detected. Action potentials were recorded by use of a conventional microelectrode. (Ca (2+))(i) was monitored by the fluorescent calcium indicator Fluo-4. RESULTS: E-4031, 4-AP, tetra-ethylammonium and quinidine induced phosphorylation of ERK. 4-Aminopyridine prolonged the duration of action potentials by 37% and increased (Ca (2+))(i) by 52% at 1 mmol/l. Pre-incubation of ethyleneglycoltetraacetic acid, 1,2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis and diltiazem completely blocked this phosphorylation, whereas flufenamic acid and benzamil did not. 4-Aminopyridine induced tyrosine phosphorylation of Pyk2 and EGFR, which peaked at 5 and 10 min, respectively. Cytochalasin D, AG1478 and dominant-negative EGFR strongly inhibited the phosphorylation of ERK, whereas calphostin C, calmidazolium and KN62 did not. CONCLUSIONS: These findings indicate that KBs induce ERK activation, which starts with Ca (2+) entry through the L-type Ca (2+) channel in cardiomyocytes, and that EGFR and Pyk2 are involved in this activation. |
| quinidine |
Oatp2 |
False Positive |
11883641 |
Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. PURPOSE: The purpose of the present study is to examine the selectivity of various inhibitors towards the rat organic anion transporting polypeptides 1 (Oatp1: gene symbol Slc21a1) and 2 (Oatp2: Slc21a5). Methods: The inhibitory effects of 20 compounds on the Oatpl-mediated transport of estradiol 17beta-D-glucuronide and on the Oatp2-mediated transport of digoxin were examined in cDNA-transfected LLC-PK1cells. RESULTS: Among the compounds examined in this study, nonsteroidal anti-inflammatory drugs, deoxycorticosterone. and quinidine preferentially inhibited Oatpl. whereas digoxin, quinine, and rifampicin preferentially inhibited Oatp2 at low concentrations. On the other hand, propionic acid, re-ketoglutarate and p-aminohippurate showed no inhibitory effects on either transporter up to a concentration of 1,000 microM. The Ki values of ibuprofen and quinidine were estimated to be 19 and 13 times lower for Oatpl compared with Oatp2, whereas the values for rifampicin, quinine, and digoxin were 13, 20, and 100 < times lower for Oatp2 compared with Oatpl. CONCLUSIONS: At low concentrations, some of the tested inhibitors exert selective inhibition of either Oatpl- or Oatp2-mediated substrate transport. These selective inhibitors may be used at appropriate concentrations to estimate the maximum contribution of Oatp1 or Oatp2 to the total substrate uptake into rat hepatocytes. |
| quinidine |
ERK-4 |
True Positive |
11691539 |
Tahara S, Fukuda K, Kodama H, Kato T, Miyoshi S, Ogawa S: Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes. J Am Coll Cardiol. 2001 Nov 1;38(5):1554-63. OBJECTIVES: We sought to determine whether potassium (K (+)) channel blockers (KBs) can activate extracellular signal-regulated kinase (ERK) and to characterize the upstream signals leading to ERK activation in cardiomyocytes. BACKGROUND: Because KBs attenuate K (+) outward current, they may possibly prolong the duration of action potentials, leading to an increase in calcium (Ca (2+)) transient ([Ca (2+)](i)) in cardiomyocytes. Elevation of intracellular Ca (2+) levels can trigger various signaling events. Influx of Ca (2+) through L-type Ca (2+) channels after membrane depolarization induced activation of MEK and ERK through activation of Ras in neurons. Although KBs are frequently used to treat cardiac arrhythmias, their effect on signaling pathways remains unknown. METHODS: Primary cultured rat cardiomyocytes were stimulated with four different KBs-4-aminopyridine (4-AP), E-4031, tetra-ethylammonium and quinidine-and phosphorylation of ERK, proline-rich tyrosine kinase 2 (Pyk2) and epidermal growth factor receptor (EGFR) was detected. Action potentials were recorded by use of a conventional microelectrode. (Ca (2+))(i) was monitored by the fluorescent calcium indicator Fluo-4. RESULTS: E-4031, 4-AP, tetra-ethylammonium and quinidine induced phosphorylation of ERK. 4-Aminopyridine prolonged the duration of action potentials by 37% and increased (Ca (2+))(i) by 52% at 1 mmol/l. Pre-incubation of ethyleneglycoltetraacetic acid, 1,2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis and diltiazem completely blocked this phosphorylation, whereas flufenamic acid and benzamil did not. 4-Aminopyridine induced tyrosine phosphorylation of Pyk2 and EGFR, which peaked at 5 and 10 min, respectively. Cytochalasin D, AG1478 and dominant-negative EGFR strongly inhibited the phosphorylation of ERK, whereas calphostin C, calmidazolium and KN62 did not. CONCLUSIONS: These findings indicate that KBs induce ERK activation, which starts with Ca (2+) entry through the L-type Ca (2+) channel in cardiomyocytes, and that EGFR and Pyk2 are involved in this activation. |
| quinidine |
ORCTL2 |
True Positive |
9744804 |
Reece M, Prawitt D, Landers J, Kast C, Gros P, Housman D, Zabel BU, Pelletier J: Functional characterization of ORCTL2--an organic cation transporter expressed in the renal proximal tubules. FEBS Lett. 1998 Aug 21;433(3):245-50. Chromosome 11p15.5 harbors a gene or genes involved in Beckwith-Wiedemann syndrome that confer (s) susceptibility to Wilms' tumor, rhabdomyosarcoma, and hepatoblastoma. We have previously identified a transcript at 11p15.5 which encodes a putative membrane transport protein, designated organic cation transporter-like 2 (ORCTL2), that shares homology with tetracycline resistance proteins and bacterial multidrug resistance proteins. In this report, we have investigated the transport properties of ORCTL2 and show that this protein can confer resistance to chloroquine and quinidine when overexpressed in bacteria. Immunohistochemistry analyses performed with anti-ORCTL2 polyclonal antibodies on human renal sections indicate that ORCTL2 is localized on the apical membrane surface of the proximal tubules. These results suggest that ORCTL2 may play a role in the transport of chloroquine and quinidine related compounds in the kidney. |
| quinidine |
endothelin-1 |
False Positive |
8825350 |
del Pozo BF, Perez-Vizcaino F, Villamor E, Zaragoza F, Tamargo J: Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta. Br J Pharmacol. 1996 Jan;117(1):105-10. 1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10 (-6) M-3 x 10 (-4) M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca (2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10 (-4) M) and quinine (< 3 x 10 (-4) M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10 (-5) M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10 (-4) M) inhibited to a similar extent both the phasic (induced in Ca (2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner. |
| quinidine |
glycoprotein-IX |
True Positive |
7532036 |
Lopez JA, Li CQ, Weisman S, Chambers M: The glycoprotein Ib-IX complex-specific monoclonal antibody SZ1 binds to a conformation-sensitive epitope on glycoprotein IX: implications for the target antigen of quinine/quinidine-dependent autoantibodies. Blood. 1995 Mar 1;85(5):1254-8. The monoclonal antibody SZ1 is of interest for two reasons: it was used to define complex formation between glycoprotein (GP) Ib and GP IX, and its epitope is likely to be identical to that recognized by most quinine- and quinidine-dependent autoantibodies that cause thrombocytopenia. To determine the location of the epitope for SZ1 within the GP Ib-IX complex (which consists of three subunits: GP Ib alpha, GP Ib beta, and GP IX), we tested the ability of the antibody to bind transfected cells that expressed different combinations of complex subunits, and compared this binding to the binding of antibodies of known specificity. SZ1 bound to cells that expressed the entire GP Ib-IX complex in the same pattern as did AN51 (an antibody specific for GP Ib alpha). However, unlike AN51, SZ1 did not bind alpha beta cells (ie, cells that express GP Ib alpha and GP Ib beta, but not GP IX), but did bind to beta IX and alpha IX cells. We then compared the binding patterns of SZ1 and FMC25, an antibody specific for GP IX. Both bound virtually identically to cell lines that expressed every combination of two of the three GP Ib-IX complex subunits. However, the epitopes of the two antibodies were not identical, because fixation with 4% paraformaldehyde of cells that expressed GP IX destroyed the SZ1 epitope while maintaining the FMC25 epitope. Because of the ability of SZ1 to block the binding of many quinine- and quinidine-dependent antibodies, these data strongly suggest that GP IX is the component of the GP Ib-IX complex recognized by those antibodies. |
| quinidine |
neutrophil-elastase |
False Positive |
7653221 |
Bykowska K, Maslanka K, Uhrynowska M, Kopec M, Lopaciuk S: Effects of human neutrophil elastase and cathepsin G on the reactivity of platelets with antiplatelet antibodies. Acta Haematol Pol. 1995;26(2):163-70. Two human neutrophil serine proteases, elastase (HNE) and cathepsin G (CathG), are known to change the structure and hemostatic function of platelet surface membrane. The platelet membrane contains glycoproteins (GPs) which function as alloantigens, autoantigens and targets of drug-induced antibodies. The aim of this study was to investigate whether proteolysis of platelet GPs by HNE and CathG is associated with changes in the reactivity of platelets to antiplatelet antibodies. The platelet immunoreactivity was examined using the MAIPA (monoclonal antibody-specific immobilization of platelet antigens) assay and PSIFT (platelet suspension immunofluorescence test). The treatment of platelets with HNE led to a moderate increase in their reactivity to quinidine-dependent (anti-GP Ib) antibody and to a slight decline in the expression of HPA-1a. In contrast, CathG did not provoke any significant changes in platelet reactions with quinidine dependent and anti-HPA-1a antibodies. Both enzymes had no significant effect on the expression of HLA-A2, HLA-A3, HLA-B7 and HLA-B8 on platelets. |
| quinidine |
cholinesterase |
True Positive |
7624918 |
Mosca A, Onelli E, Rosti E, Paleari R, Luzzana M, Imbimbo BP: A patient-side technique for real-time measurement of acetylcholinesterase activity during monitoring of eptastigmine treatment. Ther Drug Monit. 1995 Jun;17(3):230-8. Rapid and reliable measurement of acetylcholinesterase (AChE) activity is of crucial importance to the pharmacodynamic monitoring of anticholinesterase drugs. A new assay has been developed to measure AChE from 10 microliter samples of capillary blood. AChE activity was calculated from the change in pH of the reaction medium caused by the hydrolysis of acetylcholine and measured with a highly sensitive differential pH apparatus (CL-10, Eurochem, Rome, Italy). Interference by butyrylcholinesterase was eliminated by a specific inhibitor, quinidine sulfate. The assay lasts 1 min. The coefficient of variation (CV) for replicated measurements was 2.8% (3267 U/L, n = 33). Linearity ranged from 0 to 10,000 U/L. The correlation coefficient between the new technique and Ellman's colorimetric method on washed erythrocytes was r = 0.987 (y = 1.299x - 63, n = 29). The correlation coefficient between assays on capillary and venous samples was r = 0.979 (y = 0.974x + 174, n = 47). A cross-laboratory validation study was performed in 10 centers using glycerol-stabilized hemolysates with normal and reduced AChE activity. Samples were assayed in triplicate. The within- and between-laboratory CVs for samples with normal AChE activity (6,018 U/L) were 2.2 and 8.1%, respectively. The new method was applied to a double-blind, placebo-controlled multicenter study of eptastigmine in Alzheimer patients and proved to be a simple, noninvasive, rapid, and reliable method for pharmacodynamic monitoring of this drug. |
| quinidine |
potassium-channel |
True Positive |
17515703 |
Cvetanovic I, Lin C, Ranade V, Keshavarzian A, Somberg J: The effects of quinidine and its chiral isolates on erg-1sm potassium current and correlation with gastrointestinal augmentation. Am J Ther. 2007 May-Jun;14(3):269-76. Smooth-muscle erg 1 (erg1-sm) potassium channel has been recently reported to participate in the modulation of gastrointestinal contractility. Because quinidine inhibits cardiac potassium channel and as a result augments gastrointestinal contractility, it was thought that quinidine may affect erg1-sm. Studies were undertaken to evaluate the effects of quinidine and its chiral isolates on gastrointestinal erg1-sm potassium current and correlate these effects with colon contractility. Chiral separation (high-performance liquid chromatography technique), mass spectrometry, and optical rotation determination were performed to obtain chiral isolates needed for experiments. The erg1-sm potassium channel was expressed in Xenopus oocytes, and the two-electrode patch clamp technique was employed for recording. An isolated rat colon preparation was employed to measure changes in contractility. As a result of chiral separation, two peaks were obtained with elution times of 8.31 and 8.66 minutes, both with a molecular weight of 324; the optical rotations of racemate isolates X and Y were: +258 degrees, +/-0 degrees; and +217 degrees, respectively. The percentage changes in amplitudes of colon contraction (from baseline) were determined at different concentrations of quinidine and for the two isolates in five experiments in each group. Quinidine 0.1, 1, and 10 microM increased contractility by 79 +/- 34, 125 +/- 42, and 217 +/- 51 (P < or = 0.05); for isolate X, the values were 70 +/- 20, 115 +/- 32, and 272 +/- 32 (P < or = 0.05), and for isolate Y the values were 22 +/- 12, 46 +/- 17, and 59 +/- 22. The inhibition of erg1-sm currents by quinidine was 19 +/- 4, 21 +/- 5, and 48 +/- 6 (P < or = 0.05), respectively; that by isolate X was 20 +/- 4, 23 +/- 5, and 39 +/- 7 (P < or = 0.05), and that by isolate Y was 22 +/- 4, 21 +/- 4, and 31 +/- 6. One chiral isolate and quinidine markedly augmented contractility, whereas quinidine and the two chiral isolates inhibited the erg1-sm potassium currents to a similar extent. These results suggest that erg1-sm inhibition does not explain gastrointestinal contractile augmentation caused by the quinidine racemate and its chiral isolates. |
| quinidine |
potassium-channel |
True Positive |
16138883 |
Grant AO: Electrophysiological basis and genetics of Brugada syndrome. J Cardiovasc Electrophysiol. 2005 Sep;16 Suppl 1:S3-7. Brugada syndrome is a primary arrhythmic syndrome arising in the structurally normal heart. Any proposed mechanism should account for the major features of the syndrome: localization of the ST segment and T-wave changes to the right precordial leads, association of conduction slowing at several levels, precipitation or aggravation of the major ECG changes by sodium channel-blocking drugs and the occurrence of ventricular fibrillation. Heterogeneity of repolarization across the ventricle wall plays a major role. Any agency that shifts the net current gradient during phase I outward would exaggerate the normal heterogeneity of repolarization and result in the ST segment and T-wave changes characteristic of the syndrome. When the outward current shift is marked, premature repolarization may occur in epicardial zone and the resulting gradient may precipitate reentry. The syndrome is inherited as an autosomal dominant. However, 75% of clinically affected individuals are males. In 20% of cases, the syndrome is associated with mutations of the cardiac sodium channel gene SCN5A. The mutations result in a loss-of-function as a result of the synthesis of a non-functional protein, altered protein trafficking, or change in gating. Agencies that reduce the sodium current may precipitate the characteristic ECG changes, for example, sodium channel blockers and membrane depolarization by hyperkalemia. Sympathetic stimulation may reverse the ECG changes and reduce arrhythmia recurrence. By its nonspecific potassium channel blocking action, quinidine may also reduce arrhythmia recurrence. We still do not know the basis for defect in the majority of patients with Brugada syndrome. |
| quinidine |
potassium-channel |
True Positive |
14624285 |
Cubeddu LX: QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther. 2003 Nov-Dec;10(6):452-7. A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies. |
| quinidine |
potassium-channel |
True Positive |
9067300 |
Yang T, Snyders DJ, Roden DM: Inhibition of cardiac potassium currents by the vesnarinone analog OPC-18790: comparison with quinidine and dofetilide. J Pharmacol Exp Ther. 1997 Mar;280(3):1170-5. OPC-18790 is a vesnarinone analog currently in clinical trials for treatment of heart failure. In vitro studies have shown that, in addition to its positive inotropic actions, OPC-18790 prolongs cardiac action potentials. Therefore, in this study, the effects of OPC-18790 on cardiac potassium currents were compared with those we previously observed for the blockers quinidine and dofetilide in two test systems, i.e., L-cells stably transfected with mammalian cardiac potassium channel clones (Kv1.4, Kv1.5 and Kv2.1) and mouse AT-1 cells, in which the rapidly inactivating component of the cardiac delayed rectifier (I (Kr)) is the major repolarizing current. In L-cells, 10 to 100 microM OPC-18790 reduced Kv1.4, Kv1.5 and Kv2.1 currents by <30%, whereas quinidine was a more potent blocker (EC50 < 10 microM) and the I (Kr)-specific blocker dofetilide was without effect. In contrast, in AT-1 cells, OPC-18790 blocked I (Kr) with an EC50 (0.96 +/- 0.12 microM, n = 10) similar to that of quinidine (0.9 +/- 0.2 microM). For both drugs, block was voltage dependent, increasing at positive potentials. OPC-18790 and quinidine showed no frequency dependence, implying block of resting channels and/or very rapid block of open channels; this is in contrast to dofetilide, which displayed slow onset kinetics of block. Thus, we conclude that, 1) unlike quinidine, OPC-18790 does not significantly inhibit currents obtained by expression of the cardiac potassium channel clones Kv1.4, Kv1.5 and Kv2.1; 2) like quinidine and dofetilide, OPC-18790 blocks I (Kr) in AT-1 cells, but the kinetics of block onset more closely resemble those of quinidine than dofetilide; and 3) block of I (Kr) appears to be an important mechanism underlying the action potential-prolonging properties of OPC-18790. |
| quinidine |
potassium-channel |
True Positive |
8930193 |
Yao JA, Trybulski EJ, Tseng GN: Quinidine preferentially blocks the slow delayed rectifier potassium channel in the rested state. J Pharmacol Exp Ther. 1996 Nov;279(2):856-64. We examined the effects of quinidine on a slow delayed rectifier K current induced by a human IsK cDNA (hlsK) in Xenopus oocytes. The apparent blocking potency of quinidine was lowered by membrane depolarization but enhanced by membrane hyperpolarization. After block had been established at a negative membrane voltage, depolarization induced unblock. A quaternary analog of quinidine (Q+1C) was not effective when applied extracellularly, but induced prominent and sustained hlsK suppression when injected intracellularly. The voltage dependence of hlsK suppression by intracellular Q+1C was similar to that seen with extracellular quinidine. Therefore, the quinidine binding site was accessible only from the intracellular side of the membrane. Our data can be explained by proposing that quinidine binds to an intracellular domain of the hisK or an associated subunit preferentially in the rested state, and that conformational changes associated with channel activation induce drug dissociation. Such a mechanism of action predicts that hlsK suppression by quinidine will display a "reverse use dependence" (less current suppression at more frequent depolarizations), and it can at least partly explain the rate dependence in the degree of action potential prolongation induced by quinidine. |
| quinidine |
potassium-channel |
True Positive |
8846899 |
Richards S, Hillman T, Stern M: Mutations in the Drosophila pushover gene confer increased neuronal excitability and spontaneous synaptic vesicle fusion. Genetics. 1996 Apr;142(4):1215-23. We describe the identification of a gene called pushover (push), which affects both behavior and synaptic transmission at the neuromuscular junction. Adults carrying either of two mutations in push exhibit sluggishness, uncoordination, a defective escape response, and male sterility. Larvae defective in push exhibit increased release of transmitter at the neuromuscular junction. In particular, the frequency of spontaneous transmitter release and the amount of transmitter release evoked by nerve stimulation are each increased two- to threefold in push mutants at the lowest external [Ca2+] tested (0.15 mM). Furthermore, these mutants are more sensitive than wild type to application of the potassium channel-blocking drug quinidine: following quinidine application, push mutants, but not wild-type, display repetitive firing of the motor axon, leading to repetitive muscle postsynaptic potentials. The push gene thus might affect both neuronal excitability and the transmitter release process. Complementation tests and recombinational mapping suggest that the push mutations are allelic to a previously identified P-element-induced mutation, which also causes behavioral abnormalities and male sterility. |
| quinidine |
potassium-channel |
True Positive |
8592271 |
Stern M, Blake N, Zondlo N, Walters K: Increased neuronal excitability conferred by a mutation in the Drosophila bemused gene. J Neurogenet. 1995 Nov;10(2):103-18. We have identified a new gene in Drosophila on the basis of a mutation that affects both behavior and neuronal excitability. This mutation, called bemused (bem) is the result of a P element insertion at cytological position 85D. Flies defective at bem display greatly reduced coordination, flight ability and fertility. The bem mutation also affects synaptic transmission at the larval neuromuscular junction. In particular, bem larvae display a more rapid onset of augmentation than bem+ larvae. This effect is potentiated by the potassium channel blocking drug quinidine. The increased transmitter release that occurs in bem mutants following repetitive nerve stimulation is accompanied by the appearance of extra action potentials in the motor neuron. We conclude that the bem mutation increases neuronal excitability, possibly as a result of a defect in an ion channel structural or regulatory gene. |
| quinidine |
UGT2B7 |
True Positive |
16381668 |
Uchaipichat V, Mackenzie PI, Elliot DJ, Miners JO: Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases. Drug Metab Dispos. 2006 Mar;34(3):449-56. Epub 2005 Dec 28. Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20-0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 microM) and human liver microsomes (6.1+/-1.2 microM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335+/-128 microM and 186 microM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors. |
| quinidine |
CYP2D6 |
True Positive |
17542019 |
Lin T, Pan K, Mordenti J, Pan L: In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS-based assay throughput using a one-point IC (50) method and multiplexing high-performance liquid chromatography. J Pharm Sci. 2007 May 31;. A fast and robust LC/MS-based cytochrome P450 (CYP) inhibition assay, using human liver microsomes, has been fully developed and validated for the major human liver CYPs. Probe substrates were phenacetin, diclofenac, S-mephenytoin, and dextromethorphan for CYP1A2, CYP2C9, CYP2C19, and CYP2D6, respectively. Midazolam and testosterone were chosen for CYP3A4. Furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole were identified as positive control inhibitors for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. To increase the throughput of the assay, a one-point method was developed, using data from CYP inhibition assays conducted at one concentration (i.e., 10 microM), to estimate the drug concentration at which the metabolism of the CYP probe substrate was reduced by 50% (IC (50)). The IC (50) values from the one-point assay were validated by correlating the results with IC (50) values that were obtained with a traditional eight-point concentration-response curve. Good correlation was achieved with the slopes of the trendlines between 0.95 and 1.02 and with R (2) between 0.77 and 1.0. Throughput was increased twofold by using a Cohesive multiplexing high-performance liquid chromatography system. The one-point IC (50) estimate is useful for initial compound screening, while the full concentration-response IC (50) method provides detailed CYP inhibition data for later stages of drug development. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci. |
| quinidine |
CYP2D6 |
True Positive |
17409567 |
Lin L, Huang H, Zhang P, Qi X, Zhong D: Microbial transformation of dextromethorphan by Cunninghamella blakesleeana AS 3.153. Chem Pharm Bull. 2007 Apr;55(4):658-61. The capability of Cunninghamella blakesleeana AS 3.153 to transform CYP2D6 probe drug dextromethorphan was investigated. Metabolites produced by strain AS 3.153 were detected by liquid chromatography-tandem mass spectrometry (LC-MS (n)) and the metabolite dextrorphan was identified by reference to confirm its structure. The yield of dextrorphan produced by C. blakesleeana AS 3.153 was over 90%. Quinidine, a CYP2D6 selective inhibitor, was applied to investigate its effect on biotransformation. The concentration of quinidine was 4-folds higher than that of dextromethorphan and the yield of dextrorphan was reduced by 84%, which proved there was drug metabolism enzyme similar to CYP2D6 in C. blakesleeana AS 3.153. It is concluded that C. blakesleeana AS 3.153 can be used as the suitable model strain in vitro to mimic human CYP2D6 metabolism. |
| quinidine |
CYP2D6 |
True Positive |
17364883 |
Katoh M, Yokoi T: Application of chimeric mice with humanized liver for predictive ADME. Drug Metab Rev. 2007;39(1):145-57. Much effort to extrapolate the in vivo pharmacokinetics of drugs in human from experimental animals or in vitro studies has been made by many researchers. A urokinase-type plasminogen activator+/+/severe combined immunodeficient transgenic mouse line, in which the liver could be replaced by more than 80% with human hepatocytes, was established recently in Japan. This chimeric mouse line is remarkable because the replacement is higher than any other chimeric mouse reported previously. Since the liver is the critical organ involved in the pharmacokinetics of drugs, human liver is essential for the development of new drugs. To predict the human drug metabolism and pharmacokinetics, human hepatocytes and liver microsomes are recognized as better tools and are frequently used. Thus, chimeric mice with humanized liver would have great advantages in studies on drug metabolism and pharmacokinetics. We have evaluated chimeric mice for studies on absorption, distribution, metabolism, and excretion (ADME). In the liver of the chimeric mice, human phase I and phase II enzymes were clarified to be expressed and to have a similar drug metabolizing capacity as the donor. Human specific metabolites could be detected in the serum, suggesting that the chimeric mice might be used as a human ADME model for both in vitro and in vivo studies. For predicting human drug interactions, enzyme induction and inhibition are serious problems. By the treatment with typical inducers, human CYP1A2 and CYP3A4 expressed in the liver of the chimeric mice had induction potencies. After the treatment with quinidine, a specific inhibitor of human CYP2D6, the area under the curve (AUC) of a CYP2D6 metabolite, 4'-hydroxydebrisoquin, was significantly decreased in the chimeric mice but not in the control mice. Therefore, it was indicated that the chimeric mice could be used for assessing the drug interactions via enzyme induction and inhibition. As well as drug metabolism, the drug excretion was demonstrated to be humanized because cefmetazole was mainly excreted in urine both in the chimeric mice and human but in feces in control uPA-/-/SCID mice. In this review, basic researches on ADME in the chimeric mice with humanized liver are summarized and the application of the chimeric mice for predictive ADME is proposed. |
| quinidine |
CYP2D6 |
True Positive |
16984215 |
Brown HS, Galetin A, Hallifax D, Houston JB: Prediction of in vivo drug-drug interactions from in vitro data : factors affecting prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clin Pharmacokinet. 2006;45(10):1035-50. BACKGROUND: Quantitative predictions of in vivo drug-drug interactions (DDIs) resulting from metabolic inhibition are commonly made based upon the inhibitor concentration at the enzyme active site [I] and the in vitro inhibition constant (K (i)). Previous studies have involved the use of various plasma inhibitor concentrations as surrogates for [I] along with K (i) values obtained from published literature. Although this approach has resulted in a high proportion of successful predictions, a number of falsely predicted interactions are also observed. OBJECTIVES: To focus on three issues that may influence the predictive value of the [I]/K (i) ratio approach: (i) the use of unbound K (i) (K (i,u)) values generated from standardised in vitro experiments compared with literature values; (ii) the selection of an appropriate [I]; and (iii) incorporation of the impact of intestinal metabolic inhibition for cytochrome P450 (CYP) 3A4 predictions. To this end we have selected eight inhibitors of CYP2C9, CYP2D6 and CYP3A4 and 18 victim drugs from a previous database analysis to allow prediction of 45 clinical DDI studies. METHODS: In vitro kinetic and inhibition studies were performed in human liver microsomes using prototypic probe substrates of CYP2C9 and CYP2D6, with various inhibitors (miconazole, sulfaphenazole, fluconazole, ketoconazole, quinidine, fluoxetine, fluvoxamine). The K (i) estimates obtained were corrected for non-specific microsomal binding, and the K (i,u) was incorporated into in vivo predictions using various [I] values. Predictions for CYP3A4 were based upon in vitro data obtained from a previous publication within our laboratory, and an assessment of the impact of the interaction in the gut wall is included. Predictions were validated against 45 in vivo studies and those within 2-fold of the in vivo ratio of area under the plasma concentration-time curve of the substrate, in the presence and absence of the inhibitor (AUC (i)/AUC) were considered successful. RESULTS: Predictions based upon the average systemic total plasma drug concentration ([I](av)) [incorporating the effects of parallel drug elimination pathways] and the K (i,u) value resulted in 91% of studies predicted to within 2-fold of the in vivo AUC (i)/AUC. This represents a 35% improvement in prediction accuracy compared with predictions based upon total K (i) values obtained from various published literature sources. A corresponding reduction in bias and an increase in precision were also observed compared with the use of other [I] surrogates (e.g. the total and new unbound maximum hepatic input plasma concentrations). No significant improvement in prediction accuracy was observed by incorporating consideration of gut wall inhibition for CYP3A4. CONCLUSION: DDI predictions based upon the use of K (i,u) data obtained under a set of optimal standardised conditions were significantly improved compared with predictions using in vitro data collated from various sources. The use of [I](av) as the [I] surrogate generated the most successful predictions as judged by several criteria. Incorporation of either plasma protein binding of inhibitor or gut wall CYP3A4 inhibition did not result in a general improvement of DDI predictions. |
| quinidine |
CYP2D6 |
True Positive |
16595712 |
Yu AM, Haining RL: Expression, purification, and characterization of mouse CYP2d22. Drug Metab Dispos. 2006 Jul;34(7):1167-74. Epub 2006 Apr 4. Metabolism of the prototype human CYP2D6 substrates debrisoquine and bufuralol proceeds at a much slower rate in mice; therefore, the mouse has been proposed as an animal model for the human CYP2D6 genetic deficiency. To interpret the molecular mechanism of this deficiency, a cDNA belonging to the CYP2D gene subfamily (Cyp2d22) has been cloned and sequenced from a mouse mammary tumor-derived cell line. In the current study, Cyp2d22 enzyme was overexpressed and purified from insect cells using a baculovirus-mediated system. The activity of this purified enzyme was directly compared with purified human CYP2D6 toward codeine, dextromethorphan, and methadone as substrates. Purified Cyp2d22 was found to catalyze the O-demethylation of dextromethorphan with significantly higher K (m) values (250 microM) than that (4.2 microM) exhibited by purified human CYP2D6. The K (m) for dextromethorphan N-demethylation by Cyp2d22 was found to be 418 microM, much lower than that observed with human CYP2D6 and near the K (m) for dextromethorphan N-demethylation catalyzed by CYP3A4. CYP2D6 catalyzed codeine O-demethylation, whereas Cyp2d22 and CYP3A4 mediated codeine N-demethylation. Furthermore, methadone, a known CYP3A4 substrate and CYP2D6 inhibitor, was N-demethylated by Cyp2d22 with a K (m) of 517 microM and V (max) of 4.9 pmol/pmol/min. Quinidine and ketoconazole, potent inhibitors to CYP2D6 and CYP3A4, respectively, did not show strong inhibition toward Cyp2d22-mediated dextromethorphan O- or N-demethylation. These results suggest that mouse Cyp2d22 has its own substrate specificity beyond CYP2D6-like-deficient activity. |
| quinidine |
CYP2D6 |
True Positive |
16510126 |
Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, Asanuma M, Funada M, Kiryu K, Naito S, Yoshida Y, Yamamoto S, Hanioka N: Oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes. Biochem Pharmacol. 2006 Apr 28;71(9):1377-85. Epub 2006 Feb 28. In vitro quantitative studies of the oxidative metabolism of (5-methoxy-N,N-diisopropyltryptamine, 5-MeO-DIPT, Foxy) were performed using human liver microsomal fractions and recombinant CYP enzymes and synthetic 5-MeO-DIPT metabolites. 5-MeO-DIPT was mainly oxidized to O-demethylated (5-OH-DIPT) and N-deisopropylated (5-MeO-IPT) metabolites in pooled human liver microsomes. In kinetic studies, 5-MeO-DIPT O-demethylation showed monophasic kinetics, whereas its N-deisopropylation showed triphasic kinetics. Among six recombinant CYP enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) expressed in yeast or insect cells, only CYP2D6 exhibited 5-MeO-DIPT O-demethylase activity, while CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 showed 5-MeO-DIPT N-deisopropylase activities. The apparent Km value of CYP2D6 was close to that for 5-MeO-DIPT O-demethylation, and the Km values of other CYP enzymes were similar to those of the low-Km (CYP2C19), intermediate-Km (CYP1A2, CYP2C8 and CYP3A4) and high-Km phases (CYP2C9), respectively, for N-deisopropylation in human liver microsomes. In inhibition studies, quinidine (1 microM), an inhibitor of CYP2D6, almost completely inhibited human liver microsomal 5-MeO-DIPT O-demethylation at a substrate concentration of 10 microM. Furafylline, a CYP1A2 inhibitor, quercetin, a CYP2C8 inhibitor, sulfaphenazole, a CYP2C9 inhibitor and ketoconazole, a CYP3A4 inihibitor (5 microM each) suppressed about 60%, 45%, 15% and 40%, respectively, of 5-MeO-DIPT N-deisopropylation at 50 microM substrate. In contrast, omeprazole (10 microM), a CYP2C19 inhibitor, suppressed only 10% of N-deisopropylation by human liver microsomes, whereas at the same concentration the inhibitor suppressed the reaction by recombinant CYP2C19 almost completely. These results indicate that CYP2D6 is the major 5-MeO-DIPT O-demethylase, and CYP1A2, CYP2C8 and CYP3A4 are the major 5-MeO-DIPT N-deisopropylase enzymes in the human liver. |
| quinidine |
CYP2D6 |
True Positive |
16472104 |
Yamamoto T, Suzuki A, Kohno Y, Nagata K, Yamazoe Y: Prediction of drug-drug interactions for AUCoral of high clearance drug from in vitro data: utilization of a microtiter plate assay and a dispersion model. Curr Drug Metab. 2006 Feb;7(2):135-46. The purpose of this study was to propose a new method to predict in vivo drug-drug interactions (DDIs) for a high clearance drug from in vitro data. As the high clearance drug, NE-100 (N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy) phenyl] ethylamine monohydrochloride) was used. First, approach based on I (u)/K (i) value was used for the prediction of DDIs between NE-100 and concomitant drugs. When the K (i) values (K (i-cal)) obtained from the microtiter plate (MTP) assay and the reported K (i) values (K (i-rep)) for these drugs were used to predict increases at levels of NE-100 AUC (oral) (AUC (oral) ratio), the AUC (oral) ratios from the I (u)/K (i-cal) correlated with those from the I (u)/K (i-rep). This result suggests that the K (i-cal) from the MTP assay can be used for prediction of DDIs instead of the K (i-rep) value. Second, a new approach combining the inhibition rate (R) calculated from the MTP assay and two physiological models was used to predict DDIs. When the AUC (oral) ratios of NE-100 by various drugs were predicted using the R value and the well-stirred model, the ratios were similar to those predicted using the I (u)/K (i). However, after co-administration of drugs such as quinidine, propafenone and thioridazine (potent inhibitors of CYP2D6), the NE-100 AUC (oral) ratios predicted from the dispersion model was much greater than those from well-stirred model. This result shows that application of the dispersion model to the prediction method using the R value might sensitively and precisely predict the increased levels of AUC (oral) by DDIs for high clearance drug, compared with the prediction method using I (u)/K (i) value. |
| quinidine |
CYP2D6 |
True Positive |
16192109 |
Komura H, Iwaki M: Usefulness of hepatocytes for evaluating the genetic polymorphism of CYP2D6 substrates. Xenobiotica. 2005 Jun;35(6):575-87. The usefulness of human hepatocytes for assessing CYP2D6-related genetic polymorphisms was investigated. Propranolol and propafenone, which undergo phase I and II biotransformations, were used as model substrates alongside metoprolol, which is only metabolized via oxidative pathways. The contributions of CYP2D6 to the primary metabolisms of the substrates were estimated from the quinidine-mediated inhibition of their depletion rate constants in human hepatocytes and liver microsomes. The contributions in hepatocytes were 19.2% for propranolol at 0.05 microM and 36.7--76.3% for propafenone at 0.05--1.0 microM, and smaller than the contribution in microsomes, unlike the case for metoprolol. The differences between microsomes and hepatocytes were attributable to conjugate formation. The CYP2D6 contributions in hepatocytes reflected the in vivo data. The relevance of the concentration-dependent involvement of CYP2D6 in propafenone metabolism in hepatocytes to the in vivo polymorphic profile and the applicability of hepatocytes for evaluating these polymorphisms are discussed. |
| quinidine |
CYP2D6 |
True Positive |
16019948 |
Springer D, Staack RF, Paul LD, Kraemer T, Maurer HH: Identification of cytochrome P450 enzymes involved in the metabolism of 3',4'-methylenedioxy-alpha-pyrrolidinopropiophenone (MDPPP), a designer drug, in human liver microsomes. Xenobiotica. 2005 Mar;35(3):227-37. The metabolism of 3',4'-methylenedioxy-a-pyrrolidinopropiophenone (MDPPP), a novel designer drug, to its demethylenated major metabolite 3',4'-dihydroxy-pyrrolidinopropiophenone (di-HO-PPP) was studied in pooled human liver microsomes (HLM) and in cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes. CYP2C19 catalysed the demethylenation with apparent Km and Vmax values of 120.0+/-13.4 microM and 3.2+/-0.1 pmol/min/pmol CYP, respectively (mean+/-standard deviation). CYP2D6 catalysed the demethylenation with apparent Km and Vmax values of 13.5+/-1.5 microM and 1.3+/-0.1 pmol/min/pmol CYP, respectively. HLM exhibited a clear biphasic profile with an apparent Km,1 value of 7.6+/-9.0 and a Vmax,1 value of 11.1+/-3.6 pmol/min/mg protein, respectively. Percentages of intrinsic clearances of MDPPP by specific CYPs were calculated using the relative activity factor (RAF) approach with (S)-mephenytoin-4'-hydroxylation or bufuralol-1'-hydroxylation as index reactions for CYP2C19 or CYP2D6, respectively. MDPPP, di-HO-PPP and the standard 4'-methyl-pyrrolidinohexanophenone (MPHP) were separated and analysed by liquid chromatography-mass spectrometry in the selected-ion monitoring (SIM) mode. The CYP2D6-specific chemical inhibitor quinidine (3 microM) significantly (p <0.001) inhibited di-HO-PPP formation by 75.8%+/-1.7% (mean+/-standard error of the mean) in incubation mixtures with HLM and 2 microM MDPPP. It can be concluded from the data obtained from kinetic and inhibition studies that polymorphically expressed CYP2D6 and CYP2C19 are almost equally responsible for MDPPP demethylenation. |
| quinidine |
CYP2D6 |
True Positive |
15619261 |
Kitamura A, Mizuno Y, Natsui K, Yabuki M, Komuro S, Kanamaru H: Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone. Biopharm Drug Dispos. 2005 Mar;26(2):59-65. In vitro studies were carried out to identify the major contribution of CYP2C8, CYP2D6 and CYP3A4 to the metabolism of perospirone (cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl] butyl] cyclohexane-1,2 -dicarboximide monohydrochloride dehydrate), a novel antipsychotic agent, using human liver microsomes and expressed P450 isoforms. Quinidine (a specific inhibitor of CYP2D6) did not markedly affect the metabolism of perospirone, whereas quercetin (an inhibitor of CYP2C8) and ketoconazole (an inhibitor of CYP3A4) caused a decrease in the metabolism with human liver microsomes in a concentration dependent fashion. With 10 microM quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 microM ketoconazole almost complete inhibition was apparent. Anti-CYP2C8 and anti-CYP2D6 antisera did not exert marked effects, whereas anti-CYP3A4 antiserum caused almost complete inhibition. With expressed P450s, K (m) and V (max) values were 1.09 microM and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 microM and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 microM and 61.3 pmol/min/pmol P450 for CYP3A4, respectively. These results indicated that the metabolism of perospirone in human liver was mainly catalysed by CYP3A4, and to a lesser extent CYP2C8 and CYP2D6 were responsible because kinetic data (K (m) and V (max)) of CYP2C8 and CYP2D6 suggested catalytic potential. |
| quinidine |
CYP2C19 |
False Positive |
17542019 |
Lin T, Pan K, Mordenti J, Pan L: In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS-based assay throughput using a one-point IC (50) method and multiplexing high-performance liquid chromatography. J Pharm Sci. 2007 May 31;. A fast and robust LC/MS-based cytochrome P450 (CYP) inhibition assay, using human liver microsomes, has been fully developed and validated for the major human liver CYPs. Probe substrates were phenacetin, diclofenac, S-mephenytoin, and dextromethorphan for CYP1A2, CYP2C9, CYP2C19, and CYP2D6, respectively. Midazolam and testosterone were chosen for CYP3A4. Furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole were identified as positive control inhibitors for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. To increase the throughput of the assay, a one-point method was developed, using data from CYP inhibition assays conducted at one concentration (i.e., 10 microM), to estimate the drug concentration at which the metabolism of the CYP probe substrate was reduced by 50% (IC (50)). The IC (50) values from the one-point assay were validated by correlating the results with IC (50) values that were obtained with a traditional eight-point concentration-response curve. Good correlation was achieved with the slopes of the trendlines between 0.95 and 1.02 and with R (2) between 0.77 and 1.0. Throughput was increased twofold by using a Cohesive multiplexing high-performance liquid chromatography system. The one-point IC (50) estimate is useful for initial compound screening, while the full concentration-response IC (50) method provides detailed CYP inhibition data for later stages of drug development. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci. |
| quinidine |
CYP2C19 |
False Positive |
16035375 |
Fuhr U, Kober S, Zaigler M, Mutschler E, Spahn-Langguth H: Rate-limiting biotransformation of triamterene is mediated by CYP1A2. . Int J Clin Pharmacol Ther. 2005 Jul;43(7):327-34. OBJECTIVE: Triamterene (TA), a potassium-sparing diuretic, is extensively metabolized by hydroxylation in 4'-position and subsequent conjugation by cytosolic sulfotransferases. To identify the cytochrome P450 enzyme (s) catalyzing hydroxylation of triamterene (the rate-limiting step in the formation of the sulfate ester (STA)), in vitro incubation studies were performed with human liver microsomes. METHODS: Initial rates of TA hydroxylation (0 - 300 microM) were determined during a ten-minute-incubation period with liver microsomes of two donors. The role of individual CYP enzymes was determined by pre-incubation with selective inhibitors/alternative substrates. Vice versa, the effect of TA (0 - 500 microM) on 3-demethylation of caffeine (0 - 1,000 microM) was assessed. Metabolite concentrations were estimated by reversed-phase HPLC methods. RESULTS: TA Km values without inhibitors were 60 and 142 microM, Vmax was 177 and 220 pmol/min/mg protein, respectively. Mean inhibitor induced changes of 4'-hydroxy-TA formation were as follows: Furafylline 25 microM (CYP1A2), complete inhibition (-100%); omeprazole 250 microM (CYP1A2 inhibitor/CYP2C 19 substrate), -30%; coumarin 25 microM (CYP2A6), -11%; quinidine 25 microM (CYP2D6), -9%; ketoconazole 25 microM (CYP3A), -18%; and erythromycin 250 microM (CYP3A), -8%. In the reverse inhibition studies, TA competitively inhibited caffeine 3-demethylation with Ki values of 65 and 111 microM, respectively. CONCLUSION: 4'-hydroxylation of TA in humans appears to be mediated exclusively by CYP1A2. Inhibition or induction of CYP1A2 will change the time course of both TA and its active phase-II metabolite. The net pharmacodynamic effect of such changes is difficult to predict and needs to be evaluated in clinical studies. |
| quinidine |
CYP2C19 |
False Positive |
11128045 |
Chung WG, Park CS, Roh HK, Lee WK, Cha YN: Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol. 2000 Oct;84(2):213-20. Rat and human liver microsomes oxidized ranitidine to its N-oxide (66-76%) and S-oxide (13-18%) and desmethylranitidine (12-16%). N- and S-oxidations of ranitidine were inhibited by metimazole [flavin-containing monooxygenase (FMO) inhibitor] to 96-97% and 71-85%, respectively, and desmethylation of ranitidine was inhibited by SKF525A [cytochrome P450 (CYP) inhibitor] by 71-95%. Recombinant FMO isozymes like FMO1, FMO2, FMO3 and FMO5 produced 39, 79, 2180 and 4 ranitinine N-oxide and 45, 0, 580 and 280 ranitinine S-oxide pmol x min (-1) x nmol (-1) FMO, respectively. Desmethyranitinine was not produced by recombinant FMOs. Production of desmethylranitidine by rat and human liver microsomes was inhibited by tranylcypromine, a-naphthoflavon and quinidine, which are known to inhibit CYP2C19, 1A2 and 2D6, repectively. FMO3, the major form in adult liver, produced both ranitidine N- and S-oxides at a 4 to 1 ratio. FMO1, expressed primarily in human kidney, was 55- and 13-fold less efficient than the hepatic FMO3 in producing ranitidine N- and S-oxides, respectively. FMO2 and FMO5, although expressed slightly in human liver, kidney and lung, were not efficient producers of ranitidine N- and S-oxides. Thus, urinary contents of ranitidine N-oxide can be used as the in vivo probe to determine the hepatic FMO3 activity. |
| quinidine |
CYP2C19 |
False Positive |
10492058 |
Damkier P, Hansen LL, Brosen K: Effect of fluvoxamine on the pharmacokinetics of quinidine. Eur J Clin Pharmacol. 1999 Aug;55(6):451-6. OBJECTIVE: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. METHODS: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. RESULTS: The results showed a statistically significant median reduction of 2944% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine. CONCLUSIONS: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P4503A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. |
| quinidine |
CYP2C19 |
False Positive |
10421620 |
Tyndale RF, Li Y, Li NY, Messina E, Miksys S, Sellers EM: Characterization of cytochrome P-450 2D1 activity in rat brain: high-affinity kinetics for dextromethorphan. Drug Metab Dispos. 1999 Aug;27(8):924-30. We investigated the enzymatic function, stability, and regional distribution of rat brain cytochrome P-450 (CYP) 2D1 activity. CYP2D1 is the homolog of human CYP2D6, a genetically variable enzyme that activates or inactivates many clinical drugs acting on the central nervous system (e.g., antidepressants, monoamine oxidase inhibitors, serotonin uptake inhibitors, and neuroleptics), drugs of abuse (e.g., amphetamine and codeine), neurotoxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3, 4-tetrahydroquinoline), and endogenous neurochemicals (e.g., tryptamine). The CYP2D family has been identified in rodent, canine, and primate brain. Conversion of dextromethorphan to dextrorphan by rat brain membranes was assayed by HPLC and was dependent on NADPH, protein concentration, and incubation time. Significant loss of activity was observed in some homogenizing buffers and after freezing of whole tissues or membrane preparations. Dextromethorphan (0.5-640 microM) metabolism was mediated by high- and low-affinity enzyme systems; K (m1) was 2.7 +/- 2.6 and K (m2) was 757 +/- 156 microM (n = 3 rats, mean +/- S.E.). The enzyme activity was significantly (p <.01) and stereoselectively inhibited by CYP2D1 inhibitors quinine and quinidine (not by CYP2C or CYP3A inhibitors), and by anti-CYP2D6 peptide antiserum (not by anti-CYP2C, -CYP2B, or -CYP3A antibodies). The enzymatic activity demonstrated significant brain regional variation (n = 10 regions, p <.001). These data characterize CYP2D1-mediated dextromethorphan metabolism in rat brain and suggest that localized metabolism of other CYP2D1 substrates (drugs, neurotoxins, and possibly endogenous compounds) within the brain will occur. In humans, CYP2D6 is genetically polymorphic; the variable expression of brain CYP2D6 may result in interindividual differences in central drug and neurotoxin metabolism, possibly contributing to interindividual differences in drug effects and neurotoxicity. |
| quinidine |
CYP2C19 |
False Positive |
8819299 |
Ono S, Hatanaka T, Hotta H, Satoh T, Gonzalez FJ, Tsutsui M: Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. Xenobiotica. 1996 Jul;26(7):681-93. 1. We evaluated the specificity of 15 substrates and 14 inhibitors of the cytochrome P450s using nine human P450 forms expressed in HepG2 cells using a recombinant vaccinia virus and also in human liver microsomes. 2. Coumarin, 7-ethoxyresorufin, 7-benzyloxyresorufin, tolbutamide, aniline and diazepam were form-selective substrates towards CYP2A6, the CYP1A subfamily, CYP2B6, the CYP2C subfamily, CYP2E1 and the CYP3A subfamily respectively. However, a selective substrate for CYP2D6 was not found among the chemicals tested. 3. SKF-525A inhibited > 40% of the metabolic activity of all substrates tested, and the inhibitory effects differed among P450 forms. Sulphaphenazole, 7,8-benzoflavone, quinidine and troleandomycin were selective inhibitors of the CYP2C subfamily (except CYP2C19), the CYP1A subfamily, CYP2D6 and the CYP3A subfamily respectively. Methoxsalen (CYP2A6 inhibitor) inhibited the metabolic activity of CYP1A2 as well as that of CYP2A6. Diethyldithiocarbamate (CYP2E1 inhibitor) inhibited the metabolic activities of CYP2A6 and CYP2C19 in addition to that of CYP2E1. 4. Our results indicated that substrates and inhibitors reported as P450 selective probes are not necessarily specific for individual human P450 forms. These results may provide useful information regarding human P450 substrates and inhibitors in vitro using human liver microsomal samples. |
| quinidine |
c-myc |
True Positive |
12353235 |
Melkoumian ZK, Martirosyan AR, Strobl JS: Myc protein is differentially sensitive to quinidine in tumor versus immortalized breast epithelial cell lines. Int J Cancer. 2002 Nov 1;102(1):60-9. Quinidine regulates growth and differentiation in human breast tumor cells, but the immortalized mammary epithelial MCF-10A cell line is insensitive to quinidine. We found that a morphologically similar differentiation response was evoked by quinidine and c-myc antisense oligonucleotides in MCF-7 cells and this prompted us to investigate the actions of quinidine on c-myc gene expression. Myc protein levels were suppressed in human breast tumor cell lines, but not in MCF-10A cells, an observation that supports the hypothesis that suppression of c-myc gene expression is involved in the preferential growth and differentiation response of breast tumor cells to quinidine. Quinidine reduced c-myc mRNA levels in MCF-7 cells. Acute induction of c-myc mRNA by estradiol, as well as the c-myc response to sub-cultivation in fresh serum and H-ras driven elevations in c-myc mRNA were depressed by 50-60% in the presence of quinidine. Quinidine decreased c-myc promoter activity in MCF-7 cells in a transient reporter gene assay and a 168 bp region of human c-myc promoter (-100 to +68 with respect to the P1 promoter) was sufficient to confer responsiveness to quinidine. Quinidine is a potential lead compound for developing pharmacological agents to regulate Myc. In addition, the study of quinidine-regulated events is a promising approach to unravel differentiation control pathways that become disrupted in breast cancer. |
| quinidine |
WAF1 |
True Positive |
10938272 |
Zhou Q, Melkoumian ZK, Lucktong A, Moniwa M, Davie JR, Strobl JS: Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. J Biol Chem. 2000 Nov 10;275(45):35256-63. Quinidine inhibits proliferation and promotes cellular differentiation in human breast tumor epithelial cells. Previously we showed quinidine arrested MCF-7 cells in G (1) phase of the cell cycle and led to a G (1) to G (0) transition followed by apoptotic cell death. The present experiments demonstrated that MCF-7, MCF-7ras, T47D, MDA-MB-231, and MDA-MB-435 cells transiently differentiate before undergoing apoptosis in response to quinidine. The cells accumulated lipid droplets, and the cytokeratin 18 cytoskeleton was reorganized. Hyperacetylated histone H4 appeared within 2 h of the addition of quinidine to the medium, and levels were maximal by 24 h. Quinidine-treated MCF-7 cells showed elevated p21 (WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin. Quinidine did not show evidence for direct inhibition of histone deacetylase enzymatic activity in vitro. HDAC1 was undetectable in MCF-7 cells 30 min after addition of quinidine to the growth medium. The proteasome inhibitors MG-132 and lactacystin completely protected HDAC1 from the action of quinidine. We conclude that quinidine is a breast tumor cell differentiating agent that causes the loss of HDAC1 via a proteasomal sensitive mechanism. |
| quinidine |
cytochrome-P450 |
True Positive |
17019057 |
Zhang K, Kohno S, Kuroha M, Kokue E, Shimoda M: Clinical oral doses of dexamethasone decreases intrinsic clearance of quinidine, a cytochrome P450 3A substrate in dogs. J Vet Med Sci. 2006 Sep;68(9):903-7. We investigated the effect of dexamethasone (DEX) at clinical doses on the pharmacokinetics of quinidine (QN) in dogs. Dogs (5 healthy 1-year-old male beagles) were orally administered DEX once daily for 5 days at 2.5 or 7.5 mg/day. QN (2 mg/kg) was intravenously injected 3 weeks before and one day after the DEX treatment. The plasma concentration of QN was determined by high-performance liquid chromatography with fluorometric detection. Plasma concentrations of albumin and alpha (1)-acid glycoprotein (AGP) were determined by a bromocresol green method and a single immunodiffusion method, respectively. In order to calculate unbound concentrations of QN in plasma, the binding kinetics of QN in plasma was examined by an ultrafiltration method using pooled plasma from the 5 dogs when they were drug-free. Total body clearance of QN was decreased dose-dependently By the DEX treatment, although the decrease was not statistically significant. Elimination half-lives significantly increased (more than twice at 7.5 mg), and intrinsic clearance significantly decreased (about 50%). The volume of distribution increased significantly (about two-fold). Plasma levels of AGP significantly decreased, and the unbound fraction of QN in plasma significantly increased. Our results demonstrate that clinical doses of DEX significantly affect the pharmacokinetics of QN, a CYP3A substrate in dogs, by decreasing CYP3A activity and plasma AGP levels. There is a possibility that adverse drug-drug interaction occurs during DEX therapy through its effects on CYP3A activity and plasma AGP levels. |
| quinidine |
cytochrome-P450 |
True Positive |
12815613 |
Arinc E, Bozcaarmutlu A: Catalyzation of cocaine N-demethylation by cytochromes P4502B, P4503A, and P4502D in fish liver. J Biochem Mol Toxicol. 2003;17(3):169-76. Cocaine N-demethylation by microsomal cytochrome P450s is the principal pathway in cocaine bioactivation and hepatotoxicity. P450 isozymes involved in N-demethylation of cocaine have not been elucidated yet and they differ from species to species. In humans and mice, P4503A contributes to cocaine N-demethylase activity, whereas in rats, both P4503A and P4502B participate. In the present study, contribution of different P450 isozymes to cocaine N-demethylase activity was studied in vitro with fish liver microsomes. The specific cocaine N-demethylase activity was found to be 0.672 +/- 0.22 nmol formaldehyde formed/min/mg protein (mean +/- SD, n = 6). Cocaine N-demethylase exhibited biphasic kinetics, and from the Lineweaver-Burk plot, two K (m) values were calculated as 0.085 and 0.205 mM for the high- and low-affinity enzyme. These results indicate that N-demethylation of cocaine in mullet liver microsomes is catalyzed by at least two cytochrome P450 isozymes. Inhibitory effects of cytochrome P450 isozyme-selective chemical inhibitors, ketoconazole, cimetidine, SKF-525A, and quinidine, on cocaine N-demethylase activity were studied at 50, 100, and 500 micro M concentrations of these inhibitors. At 100 micro M final concentrations, ketoconazole (P4503A inhibitor), SKF-525A (inhibitor of both P4502B and P4503A), and cimetidine (P4503A inhibitor) inhibited N-demethylation activity by 73, 69, and 63%, respectively. Quinidine, P4502D-specific inhibitor, at 100 micro M final concentration, reduced N-demethylation activity down to 64%. Aniline, a model substrate for P4502E1, did not alter N-demethylase activity in the final concentration of 100 micro M. IC (50) values were calculated to be 20 micro M for ketoconazole, 48 micro M for cimetidine (both specific P4503A inhibitors), 164 micro M for quinidine (P4502D inhibitor), and 59 micro M for SKF-525A (inhibitor of both P4503A and P4502B). The contribution of P4502B to cocaine N-demethylase activity in mullet liver microsomes was further explored by the use of purified mullet cytochrome P4502B in the reconstituted system containing purified mullet P450 reductase and lipid. The turnover number was calculated as 4.2 nmol HCOH/(min nmol P450). Overall, these results show that P4503A and P4502B are the major P450s responsible for N-demethylation of cocaine, whereas contribution of P4502D is a minor one, and P4502E1 is not involved in the N-demethylation of cocaine in mullet liver microsomes. |
| quinidine |
cytochrome-P450 |
True Positive |
12381722 |
Hoffmann L, Maury S, Martz F, Geoffroy P, Legrand M: Purification, cloning, and properties of an acyltransferase controlling shikimate and quinate ester intermediates in phenylpropanoid metabolism. J Biol Chem. 2003 Jan 3;278(1):95-103. Epub 2002 Oct 14. A protein hydrolyzing hydroxycinnamoyl-CoA esters has been purified from tobacco stem extracts by a series of high pressure liquid chromatography steps. The determination of its N-terminal amino acid sequence allowed design of primers permitting the corresponding cDNA to be cloned by PCR. Sequence analysis revealed that the tobacco gene belongs to a plant acyltransferase gene family, the members of which have various functions. The tobacco cDNA was expressed in bacterial cells as a recombinant protein fused to glutathione S-transferase. The fusion protein was affinity-purified and cleaved to yield the recombinant enzyme for use in the study of catalytic properties. The enzyme catalyzed the synthesis of shikimate and quinate esters shown recently to be substrates of the cytochrome P450 3-hydroxylase involved in phenylpropanoid biosynthesis. The enzyme has been named hydroxycinnamoyl-CoA: shikimate/quinate hydroxycinnamoyltransferase. We show that p-coumaroyl-CoA and caffeoyl-CoA are the best acyl group donors and that the acyl group is transferred more efficiently to shikimate than to quinate. The enzyme also catalyzed the reverse reaction, i.e. the formation of caffeoyl-CoA from chlorogenate (5-O-caffeoyl quinate ester). Thus, hydroxycinnamoyl-CoA:shikimate/quinate hydroxycinnamoyltransferase appears to control the biosynthesis and turnover of major plant phenolic compounds such as lignin and chlorogenic acid. |
| quinidine |
cytochrome-P450 |
True Positive |
10628900 |
Damkier P, Hansen LL, Brosen K: Rifampicin treatment greatly increases the apparent oral clearance of quinidine. Pharmacol Toxicol. 1999 Dec;85(6):257-62. We investigated the effect of cytochrome P450 induction by rifampicin on the in vivo oxidative metabolism of quinidine. The pharmacokinetics of a 200 mg oral single dose quinidine were studied before and after one week of daily treatment with 600 mg rifampicin in six healthy young male volunteers. Biomarker reactions of cytochrome P450 isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. The median total apparent oral clearance and partial clearance by 3-hydroxylation of quinidine increased 9 times. The partial clearance by N-oxidation increased 6 times. The Cmax and the elimination half life were reduced 3 times. No statistically significant changes were found for quinidine tmax and renal clearance. The cortisol metabolic ratio increased 5 times, while no statistically significant effects were seen for other CYP marker reactions. The results indicate that the inductive effect of rifampicin is likely to be of clinical relevance particularly when used concomitantly with drugs metabolized by CYP3A4. |
| quinidine |
cytochrome-P450 |
True Positive |
10381752 |
Ludwig E, Schmid J, Beschke K, Ebner T: Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'-methylhydroxylation by quinidine and hydroquinidine in vitro. J Pharmacol Exp Ther. 1999 Jul;290(1):1-8. In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased Km and increased Vmax of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both Km and Vmax of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations. |
| quinidine |
cytochrome-P450 |
True Positive |
10375008 |
McKillop D, Back DJ, McCormick AD, Evans JA, Tjia J: Preclinical and in vitro assessment of the potential of D0870, an antifungal agent, for producing clinical drug interactions. Xenobiotica. 1999 Apr;29(4):395-408. 1. D0870, an azole antifungal agent, produced dose-related increases in total cytochrome P450 and aldrin epoxidase when administered as 14 daily oral doses (0, 0.5, 2.5 and 12.5 mg/kg/day) to the male rat. Administered as single doses, D0870 increased pentobarbitone-sleeping time in a dose-related manner. 2. In human hepatic microsomal incubations, D0870 produced pronounced inhibition of CYP2C9 (tolbutamide hydroxylase) and, to a lesser degree, CYP3A4 (testosterone 6beta-hydroxylase), but had more limited effects on CYP1A2, 2C19 and 2D6 activity. In comparison with ketoconazole, itraconazole and fluconazole, D0870 was the most potent inhibitor of CYP2C9 activity. It is predicted that D0870 may inhibit the in vivo clearance of CYP2C9 substrates by approximately 58%, thereby increasing their steady-state concentrations by 2.4 times, which would be of clinical significance for some compounds. 3. During incubation of [14C]-D0870 with cultured human hepatocytes for up to 72 h, two discrete metabolites (A and B) were formed. Formation of metabolite A was abolished by both quinidine and ketoconazole and is probably CYP3A4-mediated, whereas generation of metabolite B did not appear to be dependent on cytochrome P450. 4. D0870 has potential to produce both induction and inhibition of cytochrome P450 enzymes in man. |
| quinidine |
cytochrome-P450 |
True Positive |
10086984 |
Nielsen TL, Rasmussen BB, Flinois JP, Beaune P, Brosen K: In vitro metabolism of quinidine: the (3S)-3-hydroxylation of quinidine is a specific marker reaction for cytochrome P-4503A4 activity in human liver microsomes. J Pharmacol Exp Ther. 1999 Apr;289(1):31-7. The aim of this study was to evaluate the (3S)-3-hydroxylation and the N-oxidation of quinidine as biomarkers for cytochrome P-450 (CYP) 3A4 activity in human liver microsome preparations. An HPLC method was developed to assay the metabolites (3S)-3-hydroxyquinidine (3-OH-Q) and quinidine N-oxide (Q-N-OX) formed during incubation with microsomes from human liver and from Saccharomyces cerevisiae strains expressing 10 human CYPs. 3-OH-Q formation complied with Michaelis-Menten kinetics (mean values of Vmax and Km: 74.4 nmol/mg/h and 74.2 microM, respectively). Q-N-OX formation followed two-site kinetics with mean values of Vmax, Km and Vmax/Km for the low affinity isozyme of 15.9 nmol/mg/h, 76.1 microM and 0.03 ml/mg/h, respectively. 3-OH-Q and Q-N-OX formations were potently inhibited by ketoconazole, itraconazole, and triacetyloleandomycin. Isozyme specific inhibitors of CYP1A2, -2C9, -2C19, -2D6, and -2E1 did not inhibit 3-OH-Q or Q-N-OX formation, with Ki values comparable with previously reported values. Statistically significant correlations were observed between CYP3A4 content and formations of 3-OH-Q and Q-N-OX in 12 human liver microsome preparations. Studies with yeast-expressed isozymes revealed that only CYP3A4 actively catalyzed the (3S)-3-hydroxylation. CYP3A4 was the most active enzyme in Q-N-OX formation, but CYP2C9 and 2E1 also catalyzed minor proportions of the N-oxidation. In conclusion, our studies demonstrate that only CYP3A4 is actively involved in the formation of 3-OH-Q. Hence, the (3S)-3-hydroxylation of quinidine is a specific probe for CYP3A4 activity in human liver microsome preparations, whereas the N-oxidation of quinidine is a somewhat less specific marker reaction for CYP3A4 activity, because the presence of a low affinity enzyme is demonstrated by different approaches. |
| quinidine |
cytochrome-P450 |
True Positive |
9574819 |
Zeng Z, Andrew NW, Arison BH, Luffer-Atlas D, Wang RW: Identification of cytochrome P4503A4 as the major enzyme responsible for the metabolism of ivermectin by human liver microsomes. Xenobiotica. 1998 Mar;28(3):313-21. 1. Ivermectin was extensively metabolized by human liver microsomes to at least 10 metabolites. The structure of many of them (mostly hydroxylated and demethylated) was determined by 1H-NMR and LC/MS. 2. To determine which human cytochrome P450 isoform (s) is responsible for the metabolism of ivermectin, chemical inhibitors including sulphaphenazole, quinidine, furafylline, troleandomycin (TAO) and diethyldithiocarbamate (DDC) were used to evaluate their effect on ivermectin metabolism. TAO, a specific inhibitor of cytochrome P4503A4, was the most potent inhibitor, inhibiting the total metabolism as well as formation of each metabolite. Metabolism was also inhibited by an anti-human cytochrome 3A4 antibody by 90%. 3. When ivermectin was incubated with microsomes from cells expressing CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at 4 mg/ml protein concentrations, metabolic activity was only detected with the microsomes containing CYP3A4. The metabolic profile from cDNA-expressed CYP3A4 microsomes was qualitatively similar to that from human liver microsomes. 4. Thus, cytochrome P4503A4 is the predominant isoform responsible for the metabolism of ivermectin by human liver microsomes. |
| quinidine |
cytochrome-P450 |
True Positive |
9456292 |
van Breemen RB, Nikolic D, Bolton JL: Metabolic screening using on-line ultrafiltration mass spectrometry. Drug Metab Dispos. 1998 Feb;26(2):85-90. An on-line mass spectrometric method has been developed to generate and identify drug metabolites formed by hepatic cytochromes P450. This method, pulsed ultrafiltration-mass spectrometry, may be used for rapid screening of drugs to determine their extent of metabolism by microsomal cytochromes P450 and to characterize the primary metabolites. Rat liver microsomes were trapped in a stirred ultrafiltration chamber fitted with a 100,000 molecular weight cut-off ultrafiltration membrane. A continuous-flow of ammonium acetate buffer was pumped through the chamber and into an electrospray mass spectrometer. Substrates for cytochromes P450 including imipramine, chlorpromazine, and pentoxyresorufin were flow injected through the chamber along with the cofactor, NADPH, and metabolites were detected on-line by using electrospray mass spectrometry. Identical control experiments carried out using boiled microsomes or without NADPH showed no metabolite formation. Naringenin and quinidine, which are inhibitors of some isozymes of cytochrome P450 and are not known to be extensively metabolized, showed no major metabolites. For comparison, imipramine metabolites were also generated by standard batch incubation with microsomes and NADPH, followed by extraction and LC-MS analysis. Similar metabolites were obtained using the flow-through ultrafiltration method and the standard batch microsomal incubation. Tandem mass spectrometry was used to confirm structures of imipramine metabolites including 10-hydroxyimipramine, 2-hydroxyimipramine, imipramine N-oxide, and N-desmethylimipramine. Finally, the feasibility of using ultrafiltration mass spectrometry for high throughput metabolic screening was demonstrated by using on-line mass spectrometry for only 3 min per incubation instead of monitoring the entire elution profile. By carrying out multiple ultrafiltration experiments in parallel, efficient use of the mass spectrometric detector may be obtained with a throughput of at least 20 incubations per hour. Throughputs of up to 60 profiles per hour should be possible. On-line ultrafiltration electrospray mass spectrometry offers a streamlined, higher-throughput method for in vitro formation and mass spectrometric characterization of microsomal drug metabolites. |
| quinidine |
cytochrome-P450 |
True Positive |
9105395 |
Koley AP, Robinson RC, Markowitz A, Friedman FK: Drug-drug interactions: effect of quinidine on nifedipine binding to human cytochrome P450 3A4. Biochem Pharmacol. 1997 Feb 21;53(4):455-60. Quinidine is a known inhibitor of cytochrome P450-mediated nifedipine metabolism. The interactions of nifedipine and quinidine with human cytochrome P450 3A4, which metabolizes these drugs, were examined using the kinetics of CO binding to this P450 as a rapid kinetic probe of protein conformation and dynamics. This approach showed that nifedipine and quinidine bind to different P450 3A4 species, respectively termed species I and II, with distinct conformations. When both drugs were present simultaneously, nifedipine interacted with the quinidine-bound P450 species II, but not species I. These findings indicate that quinidine acts as an allosteric inhibitor by switching nifedipine binding from nifedipine-metabolizing species I to the nonmetabolizing species II. |
| quinidine |
hCE-1 |
True Positive |
12731654 |
Bailey DN, Briggs JR: Procainamide and quinidine inhibition of the human hepatic degradation of meperidine in vitro. J Anal Toxicol. 2003 Apr;27(3):142-4. Procainamide and quinidine inhibition of the degradation of meperidine in human liver was investigated by incubation of two concentrations of either drug with meperidine in homogenates of human liver over 24 and 36 h. Meperidine concentrations declined by 26% after incubation for 24 h and by 42% after incubation for 36 h. In the presence of procainamide, however, they decreased by only 15% to 18% at 24 h and by only 26% to 28% at 36 h. In the presence of quinidine, they declined by only 18% to 19% at 24 h and by only 27% to 28% at 36 h. Procainamide and quinidine may inhibit human hepatic carboxylesterase hCE-1, which is responsible for catalyzing the hydrolysis of meperidine. This inhibition may prolong the biological half-life of meperidine in patients receiving the drug together with either procainamide or quinidine. |
| quinidine |
calmodulin |
False Positive |
7543341 |
Hopp L, Bunker CH, Day BW: Quinine sensitive changes in cellular Na+ and K+ homeostasis of COS-7 cells caused by a lipophilic phenol red impurity. In Vitro Cell Dev Biol Anim. 1995 May;31(5):352-60. An impurity of phenol red (PRI) has been shown to markedly alter the intracellular Na+ and K+ homeostasis of several cell types. The effect of PRI seems to involve intracellular Ca (++)-dependent mechanisms. Using COS-7 cells as a model, we further characterized the mechanism of action of PRI by measuring cellular Na+/K+ contents and 86Rb+ efflux. Similar to human skin fibroblasts, in COS-7 cells calmodulin inhibition moderated the cationic transport effects of PRI. A TMB-8 dependent intracellular Ca++ pool does not seem to be involved in these transport events. We found no evidence for participation of the transcriptional-translational machinery in the effect of PRI. Both quinine and quinidine are able to prevent nearly all changes caused by PRI in the cellular Na+/K+ contents and 86Rb+ efflux. Although phenol red contained multiple impurities by high performance liquid chromatography (HPLC), phenolphthalein, a structurally close relative of phenol red, was free of any detectable contamination. Phenolphthalein elicited qualitatively similar transport changes to those observed during exposure to PRI. Regardless of the exact mechanism of action, we propose that the as yet unidentified substance is not a cellular toxin, rather it is a cationic transport modulator. Directly or indirectly, it may interact with the cellular Ca++/calmodulin system and activate some quinine/quinidine sensitive transport processes. This transport process is likely to be a Ca (++)-sensitive K+ channel but, due to the lack of specificity of quinine and quinidine, other transport mechanisms must be also considered. The chemical nature of PRI may be similar to phenolphthalein. |
| quinidine |
IGF-1 |
False Positive |
17520698 |
Borowiec AS, Hague F, Harir N, Guenin S, Guerineau F, Gouilleux F, Roudbaraki M, Lassoued K, Ouadid-Ahidouch H: IGF-1 activates hEAG K (+) channels through an Akt-dependent signaling pathway in breast cancer cells: Role in cell proliferation. J Cell Physiol. 2007 Sep;212(3):690-701. Previous work from our laboratory has shown that human ether a go-go (hEAG) K (+) channels are crucial for breast cancer cell proliferation and cell cycle progression. In this study, we investigated the regulation of hEAG channels by an insulin-like growth factor-1 (IGF-1), which is known to stimulate cell proliferation. Acute applications of IGF-1 increased K (+) current-density and hyperpolarized MCF-7 cells. The effects of IGF-1 were inhibited by hEAG inhibitors. Moreover, IGF-1 increased mRNA expression of hEAG in a time-dependent manner in parallel with an enhancement of cell proliferation. The MCF-7 cell proliferation induced by IGF-1 is inhibited pharmacologically by Astemizole or Quinidine or more specifically using siRNA against hEAG channel. Either mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) are known to mediate IGF-1 cell proliferative signals through the activation of extracellular signal-regulated kinase 1/2 (Erk 1/2) and Akt, respectively. In MCF-7 cells, IGF-1 rapidly stimulated Akt phosphorylation, whereas IGF-1 had little stimulating effect on Erk 1/2 which seems to be constitutively activated. The application of wortmannin was found to block the effects of IGF-1 on K (+) current. Moreover, the inhibition of Akt phosphorylation by the application of wortmannin or by a specific reduction of Akt kinase activity reduced the hEAG mRNA levels. Taken together, our results show, for the first time, that IGF-1 increases both the activity and the expression of hEAG channels through an Akt-dependent pathway. Since a hEAG channel is necessary for cell proliferation, its regulation by IGF-1 may thus play an important role in IGF-1 signaling to promote a mitogenic effect in breast cancer cells. J. Cell. Physiol. 212:690-701, 2007. (c) 2007 Wiley-Liss, Inc. |
| quinidine |
ERK1 |
True Positive |
12725644 |
Touyz RM, Yao G: Up-regulation of vascular and renal mitogen-activated protein kinases in hypertensive rats is normalized by inhibitors of the Na+/Mg2+ exchanger. Clin Sci. 2003 Aug;105(2):235-42. In the present in vivo study, we have investigated whether inhibitors of the Na (+)/Mg (2+) exchanger quinidine and imipramine influence the development of hypertension and whether this is associated with modulation of mitogen-activated protein (MAP) kinase activation in arteries and kidneys of hypertensive rats. Sprague-Dawley rats were divided into four groups (n =6/group): control (vehicle), angiotensin II (Ang II; 150 ng/kg of body weight per min subcutaneously), quinidine [Ang II (150 ng/kg of body weight per min)+quinidine (5 mg/kg of body weight per day in food)] and imipramine groups [Ang II (150 ng/kg of body weight per min)+imipramine (5 mg/kg/day in food)]. Rats were studied for 3 weeks. Phosphorylation of vascular and renal extracellular-signal-regulated protein kinase 1/2 (ERK1/2), p38MAP kinase and c-Jun N-terminal kinase (JNK) were assessed using phospho-specific antibodies. Ang II increased systolic blood pressure from 112+/-5 mmHg to 215+/-9 mmHg ( P <0.01). Development of hypertension was attenuated in Ang II-infused rats treated with quinidine (173+/-6 mmHg) and imipramine (152+/-6 mmHg) (P <0.01). Phosphorylation of ERK1/2, p38MAP kinase and JNK, which were increased 2-3-fold in arteries of the Ang II group, were reduced by quinidine and imipramine (P <0.05). Activation of renal MAP kinases was also increased in the Ang II group (P <0.05). Quinidine and imipramine reduced the phosphorylation of renal ERK1/2, but did not modify renal p38MAP kinase or JNK. Our data demonstrate that Ang II induces severe hypertension in Sprague-Dawley rats and this is associated with increased phosphorylation of vascular and renal MAP kinases. Quinidine and imipramine attenuated the development of hypertension and normalized MAP kinase activity. The findings from this study suggest a possible role for the Na (+)/Mg (2+) exchanger in vascular signalling events associated with blood pressure elevation in Ang II-dependent hypertension. |
| quinidine |
CYP2C9 |
False Positive |
17542019 |
Lin T, Pan K, Mordenti J, Pan L: In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS-based assay throughput using a one-point IC (50) method and multiplexing high-performance liquid chromatography. J Pharm Sci. 2007 May 31;. A fast and robust LC/MS-based cytochrome P450 (CYP) inhibition assay, using human liver microsomes, has been fully developed and validated for the major human liver CYPs. Probe substrates were phenacetin, diclofenac, S-mephenytoin, and dextromethorphan for CYP1A2, CYP2C9, CYP2C19, and CYP2D6, respectively. Midazolam and testosterone were chosen for CYP3A4. Furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole were identified as positive control inhibitors for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. To increase the throughput of the assay, a one-point method was developed, using data from CYP inhibition assays conducted at one concentration (i.e., 10 microM), to estimate the drug concentration at which the metabolism of the CYP probe substrate was reduced by 50% (IC (50)). The IC (50) values from the one-point assay were validated by correlating the results with IC (50) values that were obtained with a traditional eight-point concentration-response curve. Good correlation was achieved with the slopes of the trendlines between 0.95 and 1.02 and with R (2) between 0.77 and 1.0. Throughput was increased twofold by using a Cohesive multiplexing high-performance liquid chromatography system. The one-point IC (50) estimate is useful for initial compound screening, while the full concentration-response IC (50) method provides detailed CYP inhibition data for later stages of drug development. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci. |
| quinidine |
CYP2C9 |
False Positive |
17132764 |
Brown HS, Griffin M, Houston JB: Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab Dispos. 2007 Feb;35(2):293-301. Epub 2006 Nov 28. Human liver microsomes have typically resulted in marked underprediction of in vivo human intrinsic clearance (CL (int)); therefore, the utility of cryopreserved hepatocytes as an alternative in vitro system has become an important issue. In this study, 10 compounds (tolbutamide, diclofenac, S-warfarin, S-mephenytoin, dextromethorphan, bufuralol, quinidine, nifedipine, testosterone, and terfenadine) were selected as substrate probes for CYP2C9, 2C19, 2D6, and 3A4, and the kinetics of metabolite formation (n = 14 pathways) were investigated in three individual lots of cryopreserved hepatocytes and in a pool of human liver microsomes. For the majority of the compounds, lower unbound K (M) or S (50) values were observed in hepatocytes compared with microsomes, on average by 50% over a 200-fold range (0.5-140 microM). Expressed on an equivalent liver weight basis, a good correlation between microsomal and hepatocyte V (max) values was observed for most pathways greater than 5 orders of magnitude (0.16-216 nmol/min/g liver). Unbound hepatocyte CL (int) (CL (int,u)) values, when scaled to the whole liver (range 0.38-4000 ml/min/kg), were on average 2.5-fold higher than microsomal CL (int,u) values, with the exception of tolbutamide and diclofenac, for which lower hepatocellular CL (int,u) values were observed. Hepatocyte predicted CL (int) values were compared with human in vivo CL (int) values, and to supplement our data, in vitro data from cryopreserved hepatocytes were collated from four other published sources. These data show that for 37 drugs, there is, on average, a 4.5-fold under-prediction of the in vivo CL (int) using cryopreserved hepatocytes, representing a significant reduction in prediction bias compared with human microsomes. |
| quinidine |
CYP2C9 |
False Positive |
16984215 |
Brown HS, Galetin A, Hallifax D, Houston JB: Prediction of in vivo drug-drug interactions from in vitro data : factors affecting prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clin Pharmacokinet. 2006;45(10):1035-50. BACKGROUND: Quantitative predictions of in vivo drug-drug interactions (DDIs) resulting from metabolic inhibition are commonly made based upon the inhibitor concentration at the enzyme active site [I] and the in vitro inhibition constant (K (i)). Previous studies have involved the use of various plasma inhibitor concentrations as surrogates for [I] along with K (i) values obtained from published literature. Although this approach has resulted in a high proportion of successful predictions, a number of falsely predicted interactions are also observed. OBJECTIVES: To focus on three issues that may influence the predictive value of the [I]/K (i) ratio approach: (i) the use of unbound K (i) (K (i,u)) values generated from standardised in vitro experiments compared with literature values; (ii) the selection of an appropriate [I]; and (iii) incorporation of the impact of intestinal metabolic inhibition for cytochrome P450 (CYP) 3A4 predictions. To this end we have selected eight inhibitors of CYP2C9, CYP2D6 and CYP3A4 and 18 victim drugs from a previous database analysis to allow prediction of 45 clinical DDI studies. METHODS: In vitro kinetic and inhibition studies were performed in human liver microsomes using prototypic probe substrates of CYP2C9 and CYP2D6, with various inhibitors (miconazole, sulfaphenazole, fluconazole, ketoconazole, quinidine, fluoxetine, fluvoxamine). The K (i) estimates obtained were corrected for non-specific microsomal binding, and the K (i,u) was incorporated into in vivo predictions using various [I] values. Predictions for CYP3A4 were based upon in vitro data obtained from a previous publication within our laboratory, and an assessment of the impact of the interaction in the gut wall is included. Predictions were validated against 45 in vivo studies and those within 2-fold of the in vivo ratio of area under the plasma concentration-time curve of the substrate, in the presence and absence of the inhibitor (AUC (i)/AUC) were considered successful. RESULTS: Predictions based upon the average systemic total plasma drug concentration ([I](av)) [incorporating the effects of parallel drug elimination pathways] and the K (i,u) value resulted in 91% of studies predicted to within 2-fold of the in vivo AUC (i)/AUC. This represents a 35% improvement in prediction accuracy compared with predictions based upon total K (i) values obtained from various published literature sources. A corresponding reduction in bias and an increase in precision were also observed compared with the use of other [I] surrogates (e.g. the total and new unbound maximum hepatic input plasma concentrations). No significant improvement in prediction accuracy was observed by incorporating consideration of gut wall inhibition for CYP3A4. CONCLUSION: DDI predictions based upon the use of K (i,u) data obtained under a set of optimal standardised conditions were significantly improved compared with predictions using in vitro data collated from various sources. The use of [I](av) as the [I] surrogate generated the most successful predictions as judged by several criteria. Incorporation of either plasma protein binding of inhibitor or gut wall CYP3A4 inhibition did not result in a general improvement of DDI predictions. |
| quinidine |
CYP2C9 |
False Positive |
10821163 |
Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, Shou M: Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica. 2000 Apr;30(4):327-43. 1. The selectivity of eight chemical inhibitors has been extensively evaluated with 10 cDNA-expressed human cytochrome P450 isoforms (CYP). The results indicate that sulphaphenazole, quinidine and alpha-naphthoflavone are selective inhibitors of CYP2C9 (IC50 = 0.5-0.7 microM), CYP2D6 (0.3-0.4 microM) and CYP1A (0.05-5 microM) respectively on the basis of the IC50, which are much lower than those of other P450 isoforms (> 10-fold). 2. Ketoconazole exhibited potent inhibition of both CYP3A4-catalysed metabolism of phenanthrene, testosterone, diazepam (IC50 = 0.03-0.5 microM) and CYP1A1-catalysed deethylation of 7-ethoxycoumarin (0.33 microM). The selectivity of ketoconazole for other P450s was highly related to the concentration used. 3. Diethyldithiocarbamate, orphenadrine and furafylline were shown separately to be less selective inhibitors of CYP2E1, CYP2B6 and CYP1A isoforms by a broad range of IC50 that overlap those observed with other P450 isoforms. 4. Furafylline, quinidine and alpha-naphthoflavone activated CYP3A4-catalysed phenanthrene metabolism by 1.7-, 2- and 15-fold respectively. 5. The selectivity of orphenadrine and ketoconazole was further examined by using inhibitory monoclonal antibodies (MAb). Inhibitory MAb specific for the individual P450 isoforms may be of greater value than chemical inhibitors. |
| quinidine |
CYP2C9 |
False Positive |
10594487 |
Damkier P, Hansen LL, Brosen K: Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol. 1999 Dec;48(6):829-38. AIMS: In vitro studies suggest that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine. METHODS: An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme activities, |