Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects

Journal of Clinical Pharmacology

Volumn 51, Issue 1, 2011, Pages 53-59

  Chung, Jae Yong ^a   Jang, Seong Bok ^a,b   Lee, Yoon Jung ^a,b   Park, Min Soo ^a   Park, Kyungsoo ^a  

^a Yonsei University   (South Korea)

^b Yonsei University College of Medicine   (South Korea)

Author keywords

CYP2B6; drug metabolism; Sibutramine

Indexed keywords

CYTOCHROME P450 2B6; DINORSIBUTRAMINE; DRUG METABOLITE; NORSIBUTRAMINE; SIBUTRAMINE; UNCLASSIFIED DRUG;

ADULT; ALLELE; AREA UNDER THE CURVE; ARTICLE; BLOOD SAMPLING; CLEARANCE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG ELIMINATION; DRUG HALF LIFE; FEMALE; GENOTYPE; HALF LIFE TIME; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; OBESITY; PHARMACOGENETICS; SINGLE DRUG DOSE; STATISTICAL SIGNIFICANCE;

ADMINISTRATION, ORAL; ADULT; ALLELES; APPETITE DEPRESSANTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; CROSS-OVER STUDIES; CYCLOBUTANES; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; GENOTYPE; HALF-LIFE; HUMANS; MALE; OXIDOREDUCTASES, N-DEMETHYLATING; YOUNG ADULT;

EID: 78650802604     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1177/0091270010362906     Document Type: Article

References (26)

1. Heal DJ, Aspley S., Prow MR, Jackson HC, Martin KF, Cheetham SC Sibutramine: a novel anti-obesity drug: a review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998 ; 22 (suppl 1). S18 - S28.
2. Hauner H., Meier M., Jockel KH, Frey UH, Siffert W. Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism. Pharmacogenetics. 2003 ; 13: 453-459.
3. Grudell AB, Sweetser S., Camilleri M., et al. A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese or overweight adults. Gastroenterology. 2008 ; 135: 1142-1154.
4. Hind ID, Mangham JE, Ghani SP, Haddock RE, Garratt CJ, Jones RW Sibutramine pharmacokinetics in young and elderly healthy subjects. Eur J Clin Pharmacol. 1999 ; 54: 847-849.
5. Abolfathi Z., Couture J., Vallee F., LeBel M., Tanguay M., Masson E. A pilot study to evaluate the pharmacokinetics of sibutramine in healthy subjects under fasting and fed conditions. J Pharm Pharm Sci. 2004 ; 7: 345-349.
6. Stock MJ Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord. 1997 ; 21 (suppl 1). S25 - S29.
7. Luscombe GP, Hopcroft RH, Thomas PC, Buckett WR The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride. Neuropharmacology. 1989 ; 28: 129-134.
8. Bae SK, Cao S., Seo KA, Kim H., Kim MJ, Shon JH, et al. Cytochrome P450 2B6 catalyzes the formation of pharmacologically active sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites in human liver microsomes. Drug Metab Dispos. 2008 ; 36: 1679-1688.
9. Kirchheiner J., Klein C., Meineke I., et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003 ; 13: 619-626.
10. Nakajima M., Komagata S., Fujiki Y., et al. Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet Genomics. 2007 ; 17: 431-445.
11. Ekhart C., Doodeman VD, Rodenhuis S., Smits PH, Beijnen JH, Huitema AD. Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa. Br J Clin Pharmacol. 2009 ; 67: 50-60.
12. Gervot L., Rochat B., Gautier JC, et al. Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics. 1999 ; 9: 295-306.
13. Zanger UM, Klein K., Saussele T., Blievernicht J., Hofmann MH, Schwab M. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics. 2007 ; 8: 743-7459.
14. Mo SL, Liu YH, Duan W., Wei MQ, Kanwar JR, Zhou SF Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6 [published online ahead of print September 1, 2009]. Curr Drug Metab.
15. Desta Z., Saussele T., Ward B., et al. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics. 2007 ; 8: 547-558.
16. Hofmann MH, Blievernicht JK, Klein K., et al. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther. 2008 ; 325: 284-292.
17. Jinno H., Tanaka-Kagawa T., Ohno A., et al. Functional characterization of cytochrome P450 2B6 allelic variants. Drug Metab Dispos. 2003 ; 31: 398-403.
18. Rotger M., Tegude H., Colombo S., et al. Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther. 2007 ; 81: 557-566. 19. Cho JY, Lim HS, Chung JY, et al. Haplotype structure and allele frequencies of CYP2B6 in a Korean population. Drug Metab Dispos. 2004 ; 32: 1341-1344.
19. Arenaz I., Vicente J., Fanlo A., et al. Haplotype structure and allele frequencies of CYP2B6 in Spaniards and Central Americans [published online ahead of print August 14, 2009]. Fundam Clin Pharmacol.
20. Hesse LM, He P., Krishnaswamy S., et al. Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics. 2004 ; 14: 225-238.
21. Loboz KK, Gross AS, Williams KM, et al. Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther. 2006 ; 80: 75-84.
22. Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Res. 1999 ; 7: 189-198.
23. Ingelman-Sundberg M., Sim SC, Gomez A., Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 ; 116: 496-526.
24. Meridia (sibutramine) [package insert]. Mt. Olive, NJ: Knoll Pharmaceutical ; 2000.
25. Miksys S., Lerman C., Shields PG, Mash DC, Tyndale RF Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 2003 ; 45: 122-132.
26. Kim KA, Song WK, Park JY Association of CYP2B6, CYP3A5, and CYP2C19 genetic polymorphisms with sibutramine pharmacokinetics in healthy Korean subjects. Clin Pharmacol Ther. 2009 ; 86: 511-518.