Fever, Hepatotoxicity, Pain
Conditions
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.
Interventions
DRUGAcetaminophen
2 x 500 mg by mouth once
Sponsors
National Institute of General Medical Sciences (NIGMS)
Tufts University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acetaminophen Plasma Clearance Association With Race/Ethnicity | 2 days | Plasma total clearance of acetaminophen in plasma measured by HPLC |
| Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity | 2 days | Acetaminophen glucuronidation partial clearance determined from plasma clearance and urinary metabolite excretion |
| Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity | 2 days | Acetaminophen sulfation partial clearance determined from plasma clearance and urinary metabolite excretion |
| Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity | 2 days | Acetaminophen oxidation partial clearance determined from plasma clearance and urinary metabolite excretion |
| Acetaminophen Plasma Clearance Association With UGT2B15 Genotype | 2 days | The association of UGT2B15 genotype with acetaminophen total clearance |
| Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype | 2 days | The association of acetaminophen glucuronidation partial clearance with UGT2B15 genotype |
| APAP Plasma Adduct Association With UGT2B15 Genotype | 2 days | The association of UGT2B15 genotype with APAP plasma adduct concentrations |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| White Subjects 2 x 500 mg acetaminophen by mouth once | 54 |
| Black Subjects 2 x 500 mg acetaminophen by mouth once | 41 |
| Total | 95 |
Baseline characteristics
| Characteristic | White Subjects | Black Subjects | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 41 Participants | 95 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 41 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 54 Participants | 0 Participants | 54 Participants |
| Sex: Female, Male Female | 20 Participants | 23 Participants | 43 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 41 |
| other Total, other adverse events | 0 / 54 | 0 / 41 |
| serious Total, serious adverse events | 0 / 54 | 0 / 41 |
Outcome results
Primary
Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity
Acetaminophen glucuronidation partial clearance determined from plasma clearance and urinary metabolite excretion
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity | 2.9 mL/min/kg |
| Black Subjects | Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity | 3.3 mL/min/kg |
p-value: 0.42Wilcoxon (Mann-Whitney)
Primary
Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype
The association of acetaminophen glucuronidation partial clearance with UGT2B15 genotype
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype | 3.8 mL/min/kg |
| Black Subjects | Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype | 2.8 mL/min/kg |
| UGT2B15*2/*2 | Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype | 2.1 mL/min/kg |
p-value: <0.0001ANOVA
Primary
Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity
Acetaminophen oxidation partial clearance determined from plasma clearance and urinary metabolite excretion
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity | 0.9 mL/min/kg |
| Black Subjects | Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity | 0.57 mL/min/kg |
Primary
Acetaminophen Plasma Clearance Association With Race/Ethnicity
Plasma total clearance of acetaminophen in plasma measured by HPLC
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Plasma Clearance Association With Race/Ethnicity | 5.3 mL/min/kg |
| Black Subjects | Acetaminophen Plasma Clearance Association With Race/Ethnicity | 5.9 mL/min/kg |
p-value: 0.52Wilcoxon (Mann-Whitney)
Primary
Acetaminophen Plasma Clearance Association With UGT2B15 Genotype
The association of UGT2B15 genotype with acetaminophen total clearance
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Plasma Clearance Association With UGT2B15 Genotype | 6.4 mL/min/kg |
| Black Subjects | Acetaminophen Plasma Clearance Association With UGT2B15 Genotype | 5.5 mL/min/kg |
| UGT2B15*2/*2 | Acetaminophen Plasma Clearance Association With UGT2B15 Genotype | 4.7 mL/min/kg |
p-value: <0.0001ANOVA
Primary
Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity
Acetaminophen sulfation partial clearance determined from plasma clearance and urinary metabolite excretion
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity | 1.4 mL/min/kg |
| Black Subjects | Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity | 1.7 mL/min/kg |
p-value: 0.06Wilcoxon (Mann-Whitney)
Primary
APAP Plasma Adduct Association With UGT2B15 Genotype
The association of UGT2B15 genotype with APAP plasma adduct concentrations
Time frame: 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| White Subjects | APAP Plasma Adduct Association With UGT2B15 Genotype | 16 mL/min/kg |
| Black Subjects | APAP Plasma Adduct Association With UGT2B15 Genotype | 19 mL/min/kg |
| UGT2B15*2/*2 | APAP Plasma Adduct Association With UGT2B15 Genotype | 27 mL/min/kg |
p-value: 0.003ANOVA