title: Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism.
abstract: 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. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. 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.
authors: Department of Pharmacology and PharmacoGenomics, Research Center, Inje University College of Medicine, Busan, South Korea.
authors: Wei
authors: W
authors: Pan
authors: Soo-Kyung
authors: SK
authors: Bae
authors: Eon-Jeong
authors: EJ
authors: Shim
authors: Sung-Eun
authors: SE
authors: Park
authors: Sang-Seop
authors: SS
authors: Lee
authors: Soo-Jin
authors: SJ
authors: Park
authors: Chang-Woo
authors: CW
authors: Yeo
authors: Hong-Hao
authors: HH
authors: Zhou
authors: Ji-Hong
authors: JH
authors: Shon
authors: Jae-Gook
authors: JG
authors: Shin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001067:Appetite Depressants / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D044466:Asian People; D017291:Clarithromycin / Q000494:pharmacology*; D000077144:Clopidogrel; D003503:Cyclobutanes / Q000378:metabolism* / Q000493:pharmacokinetics; D065702:Cytochrome P-450 CYP2B6; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001067:Appetite Depressants; D003503:Cyclobutanes; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin; D013988:Ticlopidine; C058254:sibutramine