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; = 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.

Inhibition of CYP2E1 With Propylene Glycol Does Not Protect Against Hepatocellular Injury in Human Acetaminophen Daily‐Dosing Model

“…However, recent evidence suggests a pharmacogenomic influence. For example, there is evidence that the CYP2E1*1D polymorphism results in slower APAP oxidative metabolism …”

“…For example, there is evidence that the CYP2E1*1D polymorphism results in slower APAP oxidative metabolism. 27 Alternatively, susceptibility may be because of a non-CYP-mediated mechanism, such as lower hepatic glutathione stores. In animal models, decreased glutathione stores predispose to the development of hepatocellular injury.…”

The Impact of Proximal Roux‐en‐Y Gastric Bypass Surgery on Acetaminophen Absorption and Metabolism

“…CL/F and V z /F of metabolites were not calculated. Simulations of a multiple dosing regimen (650 mg every 4 hours) were performed using the average of the estimated compartmental parameters from pre‐ and post‐RYGBS data from this study and published data from healthy volunteers …”

Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives

“…Metabolism of APAP can be influenced by genotype differences, and variations in glucuronidation are seen in different populations due to polymorphisms in the UDP-glucuronosyltransferase (UGT) enzymes. It was recently shown that UGT2B15 *2/*2 genotype subjects showed higher APAP protein-adduct concentrations than *1/*2 and *1/*1 individuals 10 . Formation of APAP protein adducts and their release into the circulation are now areas of intense study due to the clinical implications in management of patients with APAP overdose, mainly since APAP protein adducts have been suggested to be biomarkers useful for diagnosing an APAP overdose 11 .…”