WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• UDP-glucuronosyltransferase (UGT) 2B15 is a major drug glucuronidation enzyme expressed in human liver.• Oxazepam is an isoform-selective probe drug that is being used for in vitro studies of UGT2B15.• The most common UGT2B15 missense polymorphisms (D85Y and K523T) are correlated with variable oxazepam glucuronidation in human liver bank samples.• UGT2B17 is also expressed in liver and has high sequence homology and substrate specificity overlap with UGT2B15. WHAT THIS STUDY ADDS• UGT2B15 D85Y polymorphism is identified as a major determinant of oxazepam disposition, accounting for as much as 34% of interindividual variability in oxazepam apparent oral clearance.• An effect of the UGT2B15 K523T or the UGT2B17 deletion polymorphisms on oxazepam disposition could not be detected.• Provides evidence supporting the use of oxazepam as an isoform-selective in vivo probe for studies of variability in UGT2B15 activity. AIMSAlthough in vitro studies indicate that oxazepam is an isoform-selective substrate probe for UDP-glucuronosyltransferase 2B15, the utility of this drug as an in vivo probe is uncertain. The main aim of this study was to determine whether common missense polymorphisms in the UGT2B15 gene (D85Y and K523T) are associated with altered oxazepam pharmacokinetics and pharmacodynamics. We also determined the possible influence of a common deletion polymorphism in the gene encoding UGT2B17, which shows substantial substrate specificity overlap with UGT2B15. METHODSThirty healthy male subjects were administered 15 mg of oxazepam by mouth followed by plasma oxazepam concentration monitoring for 36 h, and pharmacodynamic testing for 8 h. Genotypes were determined by genomic polymerase chain reaction and commercial 5′-nuclease assays. RESULTSAllele frequencies for D85Y, K523T, UGT2B17del were 47%, 23% and 19%, respectively. Median oxazepam apparent oral clearance was significantly lower in 85YY subjects (1.62 ml min -1 kg -1) compared with 85DD subjects (3.35 ml min -1 kg -1; P = 0.003, Student-Newman-Keuls test), whereas 85DY subjects were intermediate (2.34 ml min -1 kg -1; P = 0.018 vs. 85DD, P = 0.034 vs. 85YY). Regression analysis indicated that UGT2B15 D85Y genotype accounted for 34% of interindividual variability. However, neither UGT2B15 K523T nor UGT2B17del was associated with altered oxazepam disposition. Furthermore, no differences in pharmacodynamic measures, including quantitative electroencephalography, digit-symbol substitution test, self-or observer-rated visual analogue scales, could be demonstrated for any of the polymorphisms evaluated. CONCLUSIONSThese results identify UGT2B15 D85Y as a major determinant of oxazepam clearance, and indicate that oxazepam may be useful as an in vivo probe for glucuronidation by UGT2B15.

Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; < 0.001) and glucuronidation partial clearance (by 23-48%; < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; = 0.003) and *1/*1 (by 41%; = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; = 0.041) and *1C/*1C (by 44%; = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.