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Different Effects of Clopidogrel and Clarithromycin on the Enantioselective Pharmacokinetics of Sibutramine and its Active Metabolites in Healthy Subjects
Author(s) -
Shinde Dhananjay D.,
Kim HoSook,
Choi JaeSeok,
Pan Wei,
Bae Soo Kyung,
Yeo ChangWoo,
Shon JiHong,
Kim DongHyun,
Shin Jae Gook
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.69
Subject(s) - pharmacology , clarithromycin , pharmacokinetics , enantiomer , sibutramine , cyp2b6 , chemistry , clopidogrel , cyp3a , medicine , metabolism , cyp3a4 , stereochemistry , biochemistry , antibiotics , cytochrome p450 , aspirin , weight loss , obesity
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.