Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects.
Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t(1/2)) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t(1/2) in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration-time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects.
Chung
Jae Yong
JY
Department of Pharmacology, Yonsei University College of Medicine, 250 Sungsan-ro, Seodaemun-gu, Seoul 120-752, Korea.
Jang
Seong Bok
SB
Lee
Yoon Jung
YJ
Park
Min Soo
MS
Park
Kyungsoo
K
D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D001067:Appetite Depressants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D018592:Cross-Over Studies; D003503:Cyclobutanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D055815:Young Adult
D001067:Appetite Depressants; D003503:Cyclobutanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C058254:sibutramine