Different Effects of Clopidogrel and Clarithromycin on the Enantioselective Pharmacokinetics of Sibutramine and its Active Metabolites in Healthy Subjects1. (4th February 2013)

• Record Type: Journal Article
• Authors: Shinde, Dhananjay D.; Kim, Ho‐Sook; Choi, Jae‐Seok; Pan, Wei; Bae, Soo Kyung; Yeo, Chang‐Woo; Shon, Ji‐Hong; Kim, Dong‐Hyun; Shin, Jae Gook
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 5(2013:May)
• Page Start: 550
• Page End: 558
• Publication Date: 2013-02-04
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.69
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph69-sec-0001" sec-type="section"> <p>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 <italic>CYP2B6</italic> polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of <italic>R</italic>‐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 <italic>S</italic>‐enantiomer and 1.8‐fold versus 2.0‐fold for the <italic>R</italic>‐enantiomer, respectively. The AUCs of <italic>S</italic>‐ and <italic>R</italic>‐desmethyl metabolites changed significantly during the clopidogrel phase (<italic>P</italic> < .001 and <italic>P</italic> < .001, respectively) but not during the clarithromycin phase (<italic>P</italic> = .099 and <italic>P</italic> = .090, respectively). Exposure to sibutramine was higher in subjects with the <italic>CYP2B6*6/*6</italic> genotype, but no statistical difference was observed among the <italic>CYP2B6</italic> 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.</p> </sec> </abstract>