Journal
JOURNAL OF MEDICAL TOXICOLOGY
Volume 16, Issue 2, Pages 169-176Publisher
SPRINGER
DOI: 10.1007/s13181-019-00740-z
Keywords
Acetaminophen toxicity; 4-Methylpyrazole; Hepatotoxicity; Overdose
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Funding
- NIDDK NIH HHS [F31 DK120194] Funding Source: Medline
- NIGMS NIH HHS [P30 GM118247] Funding Source: Medline
- NIH HHS [R01 DK102142] Funding Source: Medline
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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.
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