title: Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.
abstract: In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P < .001 and P < .001, respectively) but not during the clarithromycin phase (P = .099 and P = .090, respectively). Exposure to sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo.
authors: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea.
authors: Dhananjay D
authors: DD
authors: Shinde
authors: Ho-Sook
authors: HS
authors: Kim
authors: Jae-Seok
authors: JS
authors: Choi
authors: Wei
authors: W
authors: Pan
authors: Soo Kyung
authors: SK
authors: Bae
authors: Chang-Woo
authors: CW
authors: Yeo
authors: Ji-Hong
authors: JH
authors: Shon
authors: Dong-Hyun
authors: DH
authors: Kim
authors: Jae Gook
authors: JG
authors: Shin
mesh_terms: D000328:Adult; D001067:Appetite Depressants / Q000737:chemistry / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017291:Clarithromycin / Q000494:pharmacology*; D000077144:Clopidogrel; D018592:Cross-Over Studies; D003503:Cyclobutanes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D005838:Genotype; D006801:Humans; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000235:genetics; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001067:Appetite Depressants; D003503:Cyclobutanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin; D013988:Ticlopidine; C058254:sibutramine