Different Effects of Clopidogrel and Clarithromycin on the Enantioselective Pharmacokinetics of Sibutramine and its Active Metabolites in Healthy Subjects
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea.The Journal of Clinical Pharmacology (Impact Factor: 2.48). 05/2013; 53(5):1-9. DOI: 10.1002/jcph.69
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.
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ABSTRACT: The enantioselective metabolism of sibutramine was examined using human liver microsomes (HLM) and recombinant cytochrome P-450 (CYP) isoforms. This drug is metabolized to N-mono-desmethyl- (M1) and N,N-di-desmethylsibutramine (M2), and subsequent hydroxylation results in hydroxyl M1 (HM1) and hydroxyl M2 (HM2). No significant difference was noted in formation of M1from sibutramine between R- and S-sibutramine in HLM. However, S-enantiomers of M1 and M2 were preferentially metabolized to M2, HM1, and HM2compared to R-enantiomers in HLM, and intrinsic clearance (Clint) ratios of S-enantiomers/R-enantiomers were 1.97, 4.83, and 9.94 for M2, HM1, and HM2, respectively. CYP3A4 and CYP3A5 were only involved in the formation of M1, whereas CYP2B6 and CYP2C19 were responsible for all metabolic reactions of sibutramine. CYP2C19 and CYP3A5 displayed catalytic preference for S-sibutramine to S-M1, whereas CYP2B6 and CYP3A4 showed little or no stereoselectivity in metabolism of sibutramine to M1. In the case of M2 formation, CYP2B6 metabolized S-M1 more rapidly than R-M1 with a Clint ratio of 2.14. However, CYP2C19 catalyzed less S-M1 than R-M1 and the Clint ratio of S-M1 to R-M1 was 0.65. The most significant enantioselectivity was observed in formation of HM1 from M1, and HM2 from M2. CYP2B6 and CYP2C19 exhibited preferential catalysis of formation of hydroxyl metabolites from S-enantiomers rather than R-enantiomers. These results indicate that S-sibutramine was more rapidly metabolized by CYP isoforms than R-sibutramine, and that enantioselective metabolism needs to be considered in drug interactions involving sibutramine and co-administered drugs.Journal of Toxicology and Environmental Health Part A 10/2014; 77(22-24):1419-30. DOI:10.1080/15287394.2014.951758 · 2.35 Impact Factor
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ABSTRACT: The current work demonstrates a “one-pot” click synthetic procedure for the preparation of triazole bridged cyclodextrin (CD) chiral stationary phases (CSPs) and their application for efficient chiral differentiation of clopridogrel enantiomers under reversed-phase high performance liquid chromatography (HPLC). It was found that native-CD-CSP and methylated-CD-CSP afforded good enantioselectivity towards clopridogrel enantiomers with acetonitrile(ACN) /water and methanol(MeOH) /water as the mobile phases, respectively, while the more versatile phenylcarbamoylated-CD-CSP cannot resolve the enantiomers due to the steric hindrance of the bulky phenylcarbamate moieties. Solvent selection plays an important role in CSPs’ chiral recognition ability towards clopridogrel enantiomers. The 6-hydroxyl moieties on CD rims were found to participate in the chiral recognition process. The optimal chiral resolution (Rs) was improved to 1.95 by transferring the separation from 5 um native-CD-CSP to 3 um native-CD-CSP with ACN/buffer as the mobile phases.Analytical methods 07/2015; 7(15). DOI:10.1039/C5AY01365H · 1.82 Impact Factor
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