Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Pain Clinical Trial

Official title:

Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00768716
• Other study ID #: 8600
• Secondary ID: R01GM061834R01GM
• Status: Completed
• Phase: Phase 4
• Start date: December 2008
• Est. completion date: December 2013

Study information

• Verified date: May 2019
• Source: Tufts University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: December 2013
• Est. primary completion date: June 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Fever
• Hepatotoxicity
• Pain

Intervention

Drug:
• Acetaminophen
2 x 500 mg by mouth once

Locations

Country	Name	City	State
United States	Tufts Clinical Pharmacology Study Unit	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Tufts University	National Institute of General Medical Sciences (NIGMS)

Country where clinical trial is conducted

United States, 

References & Publications (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. — View Citation

Court MH, Freytsis M, Wang X, Peter I, Guillemette C, Hazarika S, Duan SX, Greenblatt DJ, Lee WM; Acute Liver Failure Study Group. The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure. J Pharmacol Exp Ther. 2013 May;345(2):297-307. doi: 10.1124/jpet.112.202010. Epub 2013 Feb 13. — View Citation

Court MH, Peter I, Hazarika S, Vasiadi M, Greenblatt DJ, Lee WM; Acute Liver Failure Study Group. Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure. Drug Metab Dispos. 2014 Jan;42(1):28-32. doi: 10.1124/dmd.113.053546. Epub 2013 Oct 8. — View Citation

Court MH, Zhu Z, Masse G, Duan SX, James LP, Harmatz JS, Greenblatt DJ. Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and Europ — View Citation

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. — View Citation

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. — View Citation

Papageorgiou I, Court MH. Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach. Biochem Pharmacol. 2017 Aug 1;137:93-106. doi: 10.1016/j.bcp.2017.04.017. Epub 2017 Apr 19. — View Citation

Papageorgiou I, Freytsis M, Court MH. Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver. Biochem Pharmacol. 2016 Oct 1;117:78-87. doi: 10.1016/j.bcp.2016.08.014. Epub 2016 Aug 13. — View Citation

Volak LP, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH. Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2013 Feb;75(2):450-62. doi: 10.1111/j.1365-2125.2012.04364.x. — View Citation

Zhao Y, Harmatz JS, Epstein CR, Nakagawa Y, Kurosaki C, Nakamura T, Kadota T, Giesing D, Court MH, Greenblatt DJ. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol. 2015 Nov;80(5):1076-85. doi: 10.1111/bcp.12644. Epub 2015 Jun 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Acetaminophen Plasma Clearance Association With Race/Ethnicity	Plasma total clearance of acetaminophen in plasma measured by HPLC	2 days
Primary	Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity	Acetaminophen glucuronidation partial clearance determined from plasma clearance and urinary metabolite excretion	2 days
Primary	Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity	Acetaminophen sulfation partial clearance determined from plasma clearance and urinary metabolite excretion	2 days
Primary	Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity	Acetaminophen oxidation partial clearance determined from plasma clearance and urinary metabolite excretion	2 days
Primary	Acetaminophen Plasma Clearance Association With UGT2B15 Genotype	The association of UGT2B15 genotype with acetaminophen total clearance	2 days
Primary	Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype	The association of acetaminophen glucuronidation partial clearance with UGT2B15 genotype	2 days
Primary	APAP Plasma Adduct Association With UGT2B15 Genotype	The association of UGT2B15 genotype with APAP plasma adduct concentrations	2 days