The UGT2B15*2 polymorphism is a major determinant of oxazepam clearance in human volunteers.

Abstract

Oxazepam is specifically glucuronidated by UGT2B15. In previous studies we have shown that a common non‐synonymous polymorphism in the UGT2B15 gene (*2, D85Y) results in lower oxazepam glucuronidation by recombinant enzyme and human liver microsomes. The goal of this study was to determine the effect of UGT2B15*2 on the pharmacokinetics of oxazepam in 30 healthy male subjects administered 15 mg oxazepam by mouth. UGT2B15 genotype frequencies were 0.20, 0.67 and 0.13 for *1/*1, *1/*2 and *2/*2, respectively. Mean (+/‐ SD) plasma oxazepam area under the curve values extrapolated to infinity were significantly higher (P<0.001, ANOVA) in *2/*2 subjects (2.50 +/‐ 0.96 ug/mL*hr) compared with *1/*2 (1.37 +/‐ 0.40) and *1/*1 (0.981 +/‐ 0.29) subjects. Furthermore, mean weight‐normalized plasma clearance values were significantly lower (P=0.003, ANOVA) in *2/*2 subjects (1.55 +/‐ 0.61 mL/min/kg) compared with *1/*2 (2.56 +/‐ 0.74) and *1/*1 (3.53 +/‐ 1.14) subjects. These results mirror our previous in vitro results and substantiate the UGT2B15*2 polymorphism as a major determinant of oxazepam clearance in vivo. (Supported by NIH grants GM‐61834, DK‐79300, AI‐058784, and AG‐017880.)