Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers
| Autor: | David J. Greenblatt, Zhaohui Zhu, Laura P. James, Jerold S. Harmatz, Michael H. Court, Gina Masse, Su X. Duan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
medicine.medical_specialty Metabolic Clearance Rate Metabolite Glucuronidation Pharmacology 030226 pharmacology & pharmacy White People Metabolism Transport and Pharmacogenomics 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sulfation Glucuronides Pharmacokinetics Gene Frequency Polymorphism (computer science) Internal medicine Genotype medicine Humans Cysteine Glucuronosyltransferase Acetaminophen Sex Characteristics Polymorphism Genetic digestive oral and skin physiology CYP2E1 Analgesics Non-Narcotic Healthy Volunteers Metabolic Detoxication Phase II Black or African American Endocrinology chemistry 030220 oncology & carcinogenesis Molecular Medicine Female Metabolic Detoxication Phase I medicine.drug Protein Binding |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 362(3) |
| ISSN: | 1521-0103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|