Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism

Abstract

1. Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin.

2. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration–time curve (AUC) of sibutramine by 163% and 255%, respectively.

3. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine.

4. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype.

5. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases.

6. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype.

7. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine.

8. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.

Keywords::

• Sibutramine and active metabolites
• clopidogrel
• clarithromycin
• drug interaction
• CYP2B6 genotype

Acknowledgments

The authors thank Yune-Jung Yoon for the drug concentration analysis, Woo-Young Kim and Eun-Yong Cha for the genotyping work.

Declaration of interest

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. R13–2007-023-00000-0) and by grants A111218-11-PG02 from the National Project for Personalized Genomic Medicine, Korea Health 21 R&D Project, Ministry for Health & Welfare, Republic of Korea.