The Influence of Sex, Ethnicity, and CYP2B6 Genotype on Bupropion Metabolism as an Index of Hepatic CYP2B6 Activity in Humans
| Autor: | Mei Ling Chen, Paul W. Stewart, Ranjit K. Thirumaran, Katarina Ilic, Erin G. Schuetz, Celeste Lindley, Roy L. Hawke, Angela D. M. Kashuba, J. Heyward Hull |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Genotype CYP2B6 Administration Oral Pharmaceutical Science Biology White People Substrate Specificity Young Adult Sex Factors Genotype-phenotype distinction Polymorphism (computer science) Internal medicine Ethnicity medicine Humans Bupropion Biotransformation Pharmacology Polymorphism Genetic Oxidoreductases N-Demethylating Hydroxybupropion Hispanic or Latino Articles Middle Aged Antidepressive Agents Black or African American Cytochrome P-450 CYP2B6 Phenotype Endocrinology Liver Pharmacogenetics Delayed-Action Preparations Linear Models Female Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 41:575-581 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.112.048108 |
| Popis: | The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use. |
| Databáze: | OpenAIRE |
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