Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Study Overview
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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.

Official Title
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Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Conditions
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Pain, Fever, Hepatotoxicity

Intervention / Treatment
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* Drug: Acetaminophen


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: White subjects<br>2 x 500 mg acetaminophen by mouth once | Drug: Acetaminophen<br>* 2 x 500 mg by mouth once<br>* Other names: Tylenol;|
| Experimental: Black subjects<br>2 x 500 mg acetaminophen by mouth once | Drug: Acetaminophen<br>* 2 x 500 mg by mouth once<br>* Other names: Tylenol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |