Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

NCT ID: NCT00768716

Last Updated: 2019-05-23

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

95 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-12-31

Study Completion Date

2013-12-31

Brief Summary

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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.

Detailed Description

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Conditions

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Pain Fever Hepatotoxicity

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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White subjects

2 x 500 mg acetaminophen by mouth once

Group Type EXPERIMENTAL

Acetaminophen

Intervention Type DRUG

2 x 500 mg by mouth once

Black subjects

2 x 500 mg acetaminophen by mouth once

Group Type EXPERIMENTAL

Acetaminophen

Intervention Type DRUG

2 x 500 mg by mouth once

Interventions

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Acetaminophen

2 x 500 mg by mouth once

Intervention Type DRUG

Other Intervention Names

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Tylenol

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

64 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role collaborator

Tufts University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Michael H Court, BVSc, PhD

Role: PRINCIPAL_INVESTIGATOR

Tufts University

Locations

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Tufts Clinical Pharmacology Study Unit

Boston, Massachusetts, United States

Site Status

Countries

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United States

References

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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. doi: 10.1124/jpet.104.081950. Epub 2005 Mar 10.

Reference Type BACKGROUND
PMID: 15761114 (View on PubMed)

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. doi: 10.1124/jpet.104.081968. Epub 2005 Mar 10.

Reference Type BACKGROUND
PMID: 15761113 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11714888 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22725836 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23408116 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24104197 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25808818 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27531059 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28433553 (View on PubMed)

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 European-American Volunteers. J Pharmacol Exp Ther. 2017 Sep;362(3):431-440. doi: 10.1124/jpet.117.242107. Epub 2017 Jun 29.

Reference Type RESULT
PMID: 28663312 (View on PubMed)

Other Identifiers

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R01GM061834

Identifier Type: NIH

Identifier Source: secondary_id

View Link

R01GM102130

Identifier Type: NIH

Identifier Source: secondary_id

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8600

Identifier Type: -

Identifier Source: org_study_id

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