Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers

Abstract

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; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; 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 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; 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.

Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Figures

Fig. 1.

Mean (± standard error) plasma concentrations of acetaminophen (APAP) and its glucuronide and sulfate metabolites (APAP-glucuronide, APAP-sulfate) at corresponding times across all subjects administered 1 g of acetaminophen by mouth.

Fig. 2.

Correlation of APAP total plasma clearance with partial urinary clearance by glucuronidation (A), sulfation (B), oxidation (C), and unchanged renal excretion (D) measured in 95 subjects (54 European-Americans and 41 African-Americans; 52 men and 43 women) administered 1 g of acetaminophen by mouth. Acetaminophen oxidation clearances are calculated from the sum of the glutathione-derived cysteinate and mercapturate metabolites. Also shown are the Spearman correlation coefficients (Rs) and associated P values.

Fig. 3.

Correlation of total acetaminophen plasma clearance (A) and partial glucuronidation clearance (B) with plasma acetaminophen protein-adduct concentrations measured in 95 subjects (54 European-Americans and 41 African-Americans; 52 men and 43 women) at 8 hours after administration of 1 g of acetaminophen by mouth. Also shown are the Spearman correlation coefficients (Rs) and associated P values.

Fig. 4.

Association of UGT2B15 genotype with acetaminophen (APAP) total plasma clearance (A) and partial urinary clearance by glucuronidation (B). Shown are box and whiskers plots of data grouped by UGT2B15 genotype, including genotypes *1/*1 (27 subjects), *1/*2 (45 subjects with total clearance data; 43 subjects with glucuronidation clearance data), and *2/*2 (22 subjects). Also shown are the P values that were significant (<0.05) for comparisons between genotype groups by ANOVA with Holm-Sidak multiple comparisons testing on log-transformed data.

Fig. 5.

Association of race (European-American or European-American) and CYP2E1*1D genotype with partial urinary clearance of acetaminophen (APAP) by oxidation. Shown are box and whiskers plots of data grouped by CYP2E1*1D genotype and race, including genotypes *1C/*1C (49 European-Americans and 22 African-Americans), *1C/*1D (4 European-Americans and 14 African-Americans), and *1D/*1D (3 African-Americans). No European-Americans had the *1D/*1D genotype. Also shown are the P values that were significant (<0.05) for the comparison between European-American and African-American subjects by t test on log-transformed data, and for comparisons between genotype groups within African-American subjects by ANOVA with Holm-Sidak multiple comparisons testing on log-transformed data.

Fig. 6.

Association of UGT2B15 genotype with APAP protein-adduct concentrations. Shown are box and whiskers plots of data grouped by UGT2B15 genotype, including genotypes *1/*1 (27 subjects), *1/*2 (44 subjects), and *2/*2 (21 subjects). Also shown are the P values that were significant (>0.05) for comparisons between genotype groups by Kruskal-Wallis ANOVA with Dunn’s multiple comparisons testing on rank-transformed data.