Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Condition(s) targeted: Pain; Fever; Hepatotoxicity

Intervention: Acetaminophen (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Tufts University

Official(s) and/or principal investigator(s):
Michael H Court, BVSc, PhD, Principal Investigator, Affiliation: Tufts University

Overall contact:
Gina Masse, Phone: 617-636-2192, Email: gina.masse@tufts.edu

Although acetaminophen is the most commonly used nonprescription drug in the USA, little is known regarding the influence of genes and race/ethnicity on acetaminophen disposition. The investigators long-term goal is to understand the causes of differences in acetaminophen disposition between people that are the result of genetic variation and ethnicity and may predispose individuals to a higher risk of acetaminophen hepatotoxicity. The aim of this particular study is to measure the rate of elimination of acetaminophen via the 3 main pathways (glucuronidation, sulfation and oxidation) in self-identified White-Americans (n=100) and African-Americans (n=100). These rates will then be correlated with selected genetic polymorphisms in genes encoding enzymes involved in acetaminophen metabolism. Two main hypotheses will be tested: 1. African-Americans eliminate acetaminophen more rapidly by glucuronidation than do White-Americans. 2. Elimination via glucuronidation, sulfation, and oxidation in subjects will be significantly correlated with the presence of polymorphisms in the UGT1A6, SULT1A1, and CYP2E1 genes, respectively.

Official title: Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Study design: Basic Science, Non-Randomized, Open Label, Parallel Assignment, Pharmacokinetics Study

Primary outcome: Acetaminophen plasma levels

Secondary outcome: Acetaminophen metabolite levels

Minimum age: 18 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- self-declared white/Caucasian

- self-declared African-American

- active

- ambulatory

- no evidence of medical disease

Exclusion Criteria:

- alcohol use of 3 or more drinks per day

- HIV or hepatitis (B or C) infection

- isoniazid

- disulfiram

- phenobarbital

- phenytoin

- carbamazepine

- rifampicin

- valproic acid

- probenecid

- St. John's Wort

Gina Masse, Phone: 617-636-2192, Email: gina.masse@tufts.edu

Tufts Clinical Pharmacology Study Unit, Boston, Massachusetts 02111, United States; Recruiting
Gina Masse, Phone: 617-636-2192

Related publications:

Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: I. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation. J Pharmacol Exp Ther. 2005 Jun;313(3):1331-9. Epub 2005 Mar 10.

Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6. Epub 2005 Mar 10.

Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther. 2001 Dec;299(3):998-1006.

Starting date: September 2008
Ending date: April 2011
Last updated: October 7, 2008