TY - JOUR T1 - The Influence of Sex, Ethnicity, and CYP2B6 Genotype on Bupropion Metabolism as an Index of Hepatic CYP2B6 Activity in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.112.048108 SP - dmd.112.048108 AU - Katarina Ilic AU - Roy L Hawke AU - Ranjit K. Thirumaran AU - Erin G. Schuetz AU - J. Heyward Hull AU - Angela D.M. Kashuba AU - Paul W. Stewart AU - Celeste M. Lindley AU - Mei-Ling Chen Y1 - 2012/12/13 UR - http://dmd.aspetjournals.org/content/early/2012/12/13/dmd.112.048108.abstract N2 - The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 expression and activity were previosuly demonstrated in vitro. Race/Ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with inter-individual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion 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 males Caucasian, African American and Hispanic females. Blood samples were obtained at 0 and 6 hours post-dose 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 log10-transformed), ANCOVA model was fitted in which the dependent variable was CYP2B6 activity represented as the log10-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 females. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in females, 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. ER -