The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers

Introduction Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochrome P450 2E1 (CYP2E1) produces the hepatotoxic metabolite, N -acetyl- p -benzoquinone imine. CYP2E1 inhibition using 4-methylpyrazole (4-MP) has been shown to prevent APAP-...

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Bibliographic Details
Published in:Journal of medical toxicology 2020-04, Vol.16 (2), p.169-176
Main Authors: Kang, A. Min, Padilla-Jones, Angela, Fisher, Erik S., Akakpo, Jephte Y., Jaeschke, Hartmut, Rumack, Barry H., Gerkin, Richard D., Curry, Steven C.
Format: Article
Language:English
Subjects:
Acetaminophen
Analgesics
Benzoquinone
Biomedical and Life Sciences
Biomedicine
Cytochrome
Cytochrome P450
Cytochromes P450
Hepatocytes
Injury prevention
Intravenous administration
Metabolism
Metabolites
Original
Original Article
Overdose
Oxidative metabolism
Pharmacology/Toxicology
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Summary:Introduction Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochrome P450 2E1 (CYP2E1) produces the hepatotoxic metabolite, N -acetyl- p -benzoquinone imine. CYP2E1 inhibition using 4-methylpyrazole (4-MP) has been shown to prevent APAP-induced liver injury in mice and human hepatocytes. This study was conducted to assess the effect of 4-MP on APAP metabolism in humans. Methods This crossover trial examined the ability of 4-MP to inhibit CYP2E1 metabolism of APAP in five human volunteers. Participants received a single oral dose of APAP 80 mg/kg, both with and without intravenous 4-MP, after which urinary and plasma oxidative APAP metabolites were measured. The primary outcome was the fraction of ingested APAP excreted as total oxidative metabolites (APAP-CYS, APAP-NAC, APAP-GSH). Results Compared with APAP alone, co-treatment with 4-MP decreased the percentage of ingested APAP recovered as oxidative metabolites in 24-hour urine from 4.48 to 0.51% (95% CI = 2.31–5.63%, p = 0.003). Plasma concentrations of these oxidative metabolites also decreased. Conclusions These results show 4-MP effectively reduced oxidative metabolism of APAP in human volunteers ingesting a supratherapeutic APAP dose. Trial Registration ClinicalTrials.gov Identifier: NCT03878693
ISSN:1556-9039
1937-6995
DOI:10.1007/s13181-019-00740-z