JPET #242107 1 Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American volunteers

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 AfricanAmericans 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 one-gram oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between AfricanAmericans and European-Americans. However, median oxidation clearance was 37% lower in AfricanAmericans versus European-Americans (0.57 versus 0.90 mL/min/kg; P=0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11 to 14%; P<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 to 27%; P<0.001) and glucuronidation partial clearance (by 23 to 48%; P<0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; P=0.003) and *1/*1 (by 41%; P=0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P=0.041) and *1C/*1C (by 44%; P=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. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on June 29, 2017 as DOI: 10.1124/jpet.117.242107 at A PE T Jornals on July 2, 2017 jpet.asjournals.org D ow nladed from