NCT00768716

Brief 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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
95

participants targeted

Target at P50-P75 for phase_4 pain

Timeline
Completed

Started Dec 2008

Longer than P75 for phase_4 pain

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

October 7, 2008

Completed
1 day until next milestone

First Posted

Study publicly available on registry

October 8, 2008

Completed
2 months until next milestone

Study Start

First participant enrolled

December 1, 2008

Completed
3.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 1, 2012

Completed
1.5 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2013

Completed
5.4 years until next milestone

Results Posted

Study results publicly available

May 8, 2019

Completed
Last Updated

May 23, 2019

Status Verified

May 1, 2019

Enrollment Period

3.5 years

First QC Date

October 7, 2008

Results QC Date

April 3, 2019

Last Update Submit

May 9, 2019

Conditions

PainFeverHepatotoxicity

Outcome Measures

Primary Outcomes (7)

  • Acetaminophen Plasma Clearance Association With Race/Ethnicity

    Plasma total clearance of acetaminophen in plasma measured by HPLC

    2 days

  • Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity

    Acetaminophen glucuronidation partial clearance determined from plasma clearance and urinary metabolite excretion

    2 days

  • Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity

    Acetaminophen sulfation partial clearance determined from plasma clearance and urinary metabolite excretion

    2 days

  • Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity

    Acetaminophen oxidation partial clearance determined from plasma clearance and urinary metabolite excretion

    2 days

  • Acetaminophen Plasma Clearance Association With UGT2B15 Genotype

    The association of UGT2B15 genotype with acetaminophen total clearance

    2 days

  • Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype

    The association of acetaminophen glucuronidation partial clearance with UGT2B15 genotype

    2 days

  • APAP Plasma Adduct Association With UGT2B15 Genotype

    The association of UGT2B15 genotype with APAP plasma adduct concentrations

    2 days

Study Arms (2)

White subjects

EXPERIMENTAL

2 x 500 mg acetaminophen by mouth once

Drug: Acetaminophen

Black subjects

EXPERIMENTAL

2 x 500 mg acetaminophen by mouth once

Drug: Acetaminophen

Interventions

AcetaminophenDRUG

2 x 500 mg by mouth once

Also known as: Tylenol
Black subjectsWhite subjects

Eligibility Criteria

Age18 Years - 64 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • self-declared white/Caucasian
  • self-declared African-American
  • active
  • ambulatory
  • no evidence of medical disease

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Tufts Clinical Pharmacology Study Unit

Boston, Massachusetts, 02111, United States

Location

Related Publications (10)

  • 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.

    PMID: 15761114BACKGROUND

  • 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.

    PMID: 15761113BACKGROUND

  • 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.

    PMID: 11714888BACKGROUND

  • 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.

    PMID: 22725836BACKGROUND

  • 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.

    PMID: 23408116BACKGROUND

  • 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.

    PMID: 24104197BACKGROUND

  • 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.

    PMID: 25808818BACKGROUND

  • 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.

    PMID: 27531059BACKGROUND

  • 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.

    PMID: 28433553BACKGROUND

  • 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.

    PMID: 28663312RESULT

MeSH Terms

Conditions

PainFever

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Neurologic ManifestationsSigns and SymptomsPathological Conditions, Signs and SymptomsBody Temperature Changes

Intervention Hierarchy (Ancestors)

AcetanilidesAnilidesAmidesOrganic ChemicalsAniline CompoundsAmines

Results Point of Contact

Title
Dr Michael H. Court
Organization
Washington State University
michael.court@wsu.edu
5093350817

Study Officials

  • Michael H Court, BVSc, PhD

    Tufts University

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
Yes

Study Design

Study Type
interventional
Phase
phase 4
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
BASIC SCIENCE
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

October 7, 2008

First Posted

October 8, 2008

Study Start

December 1, 2008

Primary Completion

June 1, 2012

Study Completion

December 1, 2013

Last Updated

May 23, 2019

Results First Posted

May 8, 2019

Record last verified: 2019-05

Locations

US(1)