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| ID | Type | Description | Link |
|---|---|---|---|
| R01GM061834 | U.S. NIH Grant/Contract | View source | |
| R01GM102130 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of General Medical Sciences (NIGMS) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| White subjects | Experimental | 2 x 500 mg acetaminophen by mouth once |
|
| Black subjects | Experimental | 2 x 500 mg acetaminophen by mouth once |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetaminophen | Drug | 2 x 500 mg by mouth once |
|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael H Court, BVSc, PhD | Tufts University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tufts Clinical Pharmacology Study Unit | Boston | Massachusetts | 02111 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15761114 | Background | 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. | |
| 15761113 | Background | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | White Subjects | 2 x 500 mg acetaminophen by mouth once Acetaminophen: 2 x 500 mg by mouth once |
| FG001 | Black Subjects | 2 x 500 mg acetaminophen by mouth once Acetaminophen: 2 x 500 mg by mouth once |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | White Subjects | 2 x 500 mg acetaminophen by mouth once |
| BG001 | Black Subjects | 2 x 500 mg acetaminophen by mouth once |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Acetaminophen Plasma Clearance Association With Race/Ethnicity | Plasma total clearance of acetaminophen in plasma measured by HPLC | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
2 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | White Subjects | 2 x 500 mg acetaminophen by mouth once | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Michael H. Court | Washington State University | 5093350817 | michael.court@wsu.edu |
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| ID | Term |
|---|---|
| D010146 | Pain |
| D005334 | Fever |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001832 | Body Temperature Changes |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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| 2 days |
| 11714888 | Background | 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. |
| 22725836 | Background | 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. |
| 23408116 | Background | 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. |
| 24104197 | Background | 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. |
| 25808818 | Background | 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. |
| 27531059 | Background | 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. |
| 28433553 | Background | 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. |
| 28663312 | Result | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
| Primary | Acetaminophen Glucuronidation Partial Clearance Association With Race/Ethnicity | Acetaminophen glucuronidation partial clearance determined from plasma clearance and urinary metabolite excretion | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
|
| Primary | Acetaminophen Sulfation Partial Clearance Association With Race/Ethnicity | Acetaminophen sulfation partial clearance determined from plasma clearance and urinary metabolite excretion | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
|
| Primary | Acetaminophen Oxidation Partial Clearance Association With Race/Ethnicity | Acetaminophen oxidation partial clearance determined from plasma clearance and urinary metabolite excretion | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
| Primary | Acetaminophen Plasma Clearance Association With UGT2B15 Genotype | The association of UGT2B15 genotype with acetaminophen total clearance | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
|
| Primary | Acetaminophen Glucuronidation Partial Clearance Association With UGT2B15 Genotype | The association of acetaminophen glucuronidation partial clearance with UGT2B15 genotype | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
|
| Primary | APAP Plasma Adduct Association With UGT2B15 Genotype | The association of UGT2B15 genotype with APAP plasma adduct concentrations | Posted | Median | Inter-Quartile Range | mL/min/kg | 2 days |
|
|
|
|
| 54 |
| 0 |
| 54 |
| 0 |
| 54 |
| EG001 | Black Subjects | 2 x 500 mg acetaminophen by mouth once | 0 | 41 | 0 | 41 | 0 | 41 |
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| Aniline Compounds |
| D000588 | Amines |