Effects of clopidogrel on the pharmacokinetics of sibutramine and its active metabolites

J Clin Pharmacol. 2011 Dec;51(12):1704-11. doi: 10.1177/0091270010388651. Epub 2011 Jan 5.

Abstract

Sibutramine is metabolized by the enzymes CYP2B6 and CYP2C19 into 2 active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine). Clopidogrel is a mechanism-based inhibitor of CYP2B6 and CYP2C19. In this study, 13 extensive metabolizers of CYP2B6 and CYP2C19 were evaluated to clarify whether clopidogrel inhibits the formation of the active metabolites of sibutramine. In the control phase, each subject received a 15-mg oral dose of sibutramine. After a washout period of 2 weeks, in the clopidogrel phase, the subjects received 300 mg of clopidogrel on the first day and then 75-mg once daily for 6 days. One hour after the last dosing of clopidogrel, all subjects received 15-mg of sibutramine. Compared with the control phase, the mean sibutramine and M1 plasma concentrations were higher after clopidogrel treatment. Clopidogrel significantly increased the half-life (242% of control phase) and area under the plasma concentration-time curve from 0 to infinity (AUC(inf)) (227% of control phase) of sibutramine and decreased the apparent oral clearance (31% of control phase) of sibutramine. Pharmacokinetic analysis showed significant increases in the AUC(inf) (162% of control phase) of M1. The CYP2B6 and CYP2C19 inhibitor clopidogrel significantly inhibited the formations of M1 from sibutramine and M2 from sibutramine by 37% and 64%, respectively. Therefore, CYP2B6 and CYP2C19 are in vivo catalysts for the formation of the 2 active metabolites of sibutramine.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Appetite Depressants / pharmacokinetics*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood Pressure / drug effects
  • Clopidogrel
  • Cyclobutanes / blood
  • Cyclobutanes / pharmacokinetics*
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Drug Interactions
  • Female
  • Genotype
  • Half-Life
  • Heart Rate / drug effects
  • Humans
  • Male
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Oxidoreductases, N-Demethylating / genetics
  • Platelet Aggregation Inhibitors / pharmacology
  • Serotonin Uptake Inhibitors / blood
  • Serotonin Uptake Inhibitors / pharmacokinetics*
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology
  • Young Adult

Substances

  • Appetite Depressants
  • Cyclobutanes
  • Platelet Aggregation Inhibitors
  • Serotonin Uptake Inhibitors
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Oxidoreductases, N-Demethylating
  • Ticlopidine
  • sibutramine