Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation

Turpeinen, Miia; Tolonen, Ari; Uusitalo, Jouko; Jalonen, Jorma; Pelkonen, Olavi; Laine, Kari

doi:10.1016/j.clpt.2005.02.010

Cited by 134 publications

(138 citation statements)

References 17 publications

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“…Besides bupropion hydroxylation, there are alternative ketonere duction pathways for bupropion elimination leading to the formation of erythro-hydrobupropion and threohydrobupropion which seems not to be mediated by CYP enzymes, and the t1/2 reported for bupropion does not represent the elimination phase but represents the distribution phase [12,19]. Therefore, it might be the inhibition of alternative ketone reduction pathways by metamizole that prolongs the t1/2 of bupropion.…”

Section: Discussionmentioning

confidence: 99%

“…Inductive or inhibitive effects on CYP2B6 activity identified by bupropion hydroxylation have been extensively studied [7][8][9][10][11][12][13], which might lead to potential drug interactions and result in unexpected clinical consequences. Until now, the effect of metamizole administration on CYP2B6-metabolized bupropion hydroxylation in humans has not previously been reported.…”

Section: Introductionmentioning

confidence: 99%

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Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite, 4-hydroxybupropion, almost exclusively by CYP2B6.• Metamizole, a pyrazolone derivative with analgesic properties, was shown in an in vitro study to increase significantly the expression of CYP2B6 and bupropion hydroxylase activity.• The effect of metamizole on bupropion hydroxylation has not been investigated and drug interactions may occur between metamizole and bupropion. WHAT THIS PAPER ADDS• Oral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects.• Dosage adjustment of bupropion may be needed in patients when metamizole is concomitantly administered. AIMSThis study aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. METHODSSixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day -1 (500 mg tablet taken three times daily) for 4 days. Serial blood samples were obtained up to 48 h after each bupropion dose. RESULTSAfter metamizole treatment relative to bupropion alone, the geometric mean ratios (GMRs) and 90% confidence interval (CI) of the AUC(0,•) ratio of 4-hydroxybupropion over bupropion were 1.99 (1.57, 2.55) for the CYP2B6*1/*1 group, 2.15 (1.53, 3.05) for the CYP2B6*1/*6 group and 1.86 (1.36, 2.57) for the CYP2B6*6/*6 group. The GMRs and 90% CI of bupropion were 0.695 (0.622, 0.774) for AUC(0,•) and 0.400 (0.353, 0.449) for Cmax, respectively. The corresponding values for 4-hydroxybupropion were 1.43 (1.28, 1.53) and 2.63 (2.07, 2.92). The t1/2 value was significantly increased for bupropion and decreased for 4-hydroxybupropion. The tmax values of bupropion and 4-hydroxybupropion were both significantly decreased. The mean percentage changes in pharmacokinetic parameters among the CYP2B6 genotype groups were not significantly different. CONCLUSIONSOral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects. Cautions should be taken when metamizole is co-administered with CYP2B6 substrate drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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“…9 Immune-mediated mechanisms via such covalent binding are believed to be associated with idiosyncratic drug-induced hepatotoxicity. 10,11 We therefore hypothesized that ticlopidine-induced hepatotoxicity might be mediated by a similar mechanism, and searched for genes encoding CYPs that catalyze the metabolic activation of ticlopidine, [12][13][14][15][16][17][18] ticlopidine-reactive metabolite(s)-detoxifying enzymes such as glutathione S-transferase, 19 and associated proteins focusing on polymorphisms that might affect enzyme activity and amino-acid substitution as well as those for which variants have been confirmed in Japanese (as published in the literature and online searchable databases). Furthermore, since there is evidence supporting a relationship between idiosyncratic drug-induced hepatotoxicity and human leukocyte antigen (HLA) genotype, [20][21][22][23][24] three HLA class I loci (HLA-A, B and C) and 3 HLA class II loci (HLA-DRB1, DQB1 and DPB1) were also investigated.…”

Section: Introductionmentioning

confidence: 99%

Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study

Hirata¹,

Takagi

Yamamoto³

et al. 2007

Pharmacogenomics J

170

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“…20) Our results reported herein are the first to our knowledge that document a significant PK drug interaction between bupropion and ticlopidine in mice. Furthermore, these findings will support future in vivo PK drug interaction studies in mice between bupropion and other CYP2B6 inhibitors.…”

mentioning

confidence: 52%

“…18,19) In humans, repeated treatment of ticlopidine increased the area under the concentration curve (AUC) and maximal plasma concentration (C max ) of bupropion by 60% and 40%, respectively. 20) Ticlopidine has also been found to be a selective, mechanismbased inhibitor of CYP2B6. 19,21) However, to date there have been no published in vivo studies in rodents studying potential drug interactions between bupropion and ticlopidine or other CYP2B6 inhibitors.…”

mentioning

confidence: 99%

Drug Interaction Study between Bupropion and Ticlopidine in Male CF-1 Mice

Molnari

Hassan

Moeller

et al. 2011

Biological & Pharmaceutical Bulletin

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Bupropion is an atypical antidepressant that is biotransformed in humans to its major active metabolite hydroxybupropion by cytochrome P450 2B6 (CYP2B6). Co-administration of bupropion with an inhibitor of CYP2B6 can result in a serious drug interaction, leading to bupropion related adverse effects (e.g. seizures). The antiplatelet agent ticlopidine has been identified as a potent in vitro inhibitor of bupropion hydroxylation, however it is unknown if it interacts in vivo in rodents. In this study we investigated the potential pharmacokinetic (PK) drug interaction between bupropion and ticlopidine in mice. Using a destructive sampling design, male CF-1 mice were administered ticlopidine 1.0 mg/kg daily for 5 d, followed by single-dose bupropion 50 mg/kg. Bupropion and hydroxybupropion levels were measured by HPLC-UV in plasma and brain tissues at 30, 60, 90, 120 and 180 min post-dose, and compared between treatment groups. There was a strong trend in both plasma and brain data towards greater bupropion levels and smaller hydroxybupropion levels in ticlopidine treated mice. Analysis of variance indicated statistical differences (pϽ Ͻ0.05) at many time points. The variance associated with the area under the curve was calculated using Bailer's method and significant differences were found between treatment groups. Taken together, the concentration time point statistical analysis followed by PK modeling demonstrate a significant PK drug interaction between bupropion and ticlopidine. To our knowledge, this is the first study to document an in vivo drug interaction between these drugs in mice. Our findings support future in vivo drug interaction studies in mice between bupropion and CYP2B6 inhibitors.

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Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation

Abstract: Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalyzed bupropion hydroxylation. Patients receiving either clopidogrel or ticlopidine are likely to require dose adjustments when treated with drugs primarily metabolized by CYP2B6.

Cited by 134 publications

References 17 publications

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study

Drug Interaction Study between Bupropion and Ticlopidine in Male CF-1 Mice

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