The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers
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.
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).
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.
These results show 4-MP effectively reduced oxidative metabolism of APAP in human volunteers ingesting a supratherapeutic APAP dose.
ClinicalTrials.gov Identifier: NCT03878693
KeywordsAcetaminophen toxicity 4-Methylpyrazole Hepatotoxicity Overdose CYP2E1
Sources of Funding
JYA and HJ were financially supported by NIH grants R01 DK102142 and P30 GM118247.
Compliance with Ethical Standards
Each participant provided informed consent and was randomized by blind draw from an envelope to start with one of two treatments (A or B), followed by crossover to the other treatment. This study was approved by the University of Arizona Institutional Review Board and registered with ClinicalTrials.gov (NCT03878693).
Conflicts of Interest
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