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Randomized Controlled Trial
. 2020 Apr;16(2):169-176.
doi: 10.1007/s13181-019-00740-z. Epub 2019 Nov 25.

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

A Min Kang  1   2 , Angela Padilla-Jones  3 , Erik S Fisher  3 , Jephte Y Akakpo  4 , Hartmut Jaeschke  4 , Barry H Rumack  5 , Richard D Gerkin  3 , Steven C Curry  6   3
Affiliations
Randomized Controlled Trial

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

A Min Kang et al. J Med Toxicol. 2020 Apr.

Abstract

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.

Keywords: 4-Methylpyrazole; Acetaminophen toxicity; CYP2E1; Hepatotoxicity; Overdose.

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Conflict of interest statement

None.

Figures

Fig. 1
Fig. 1
Twenty-four-hour urinary excretion of oxidative APAP metabolites as percent of ingested APAP dose (80 mg/kg body weight) for five participants in each of the two conditions, with mean ± SEM shown for each treatment. Panel a, APAP-CYS metabolite; panel b, APAP-NAC metabolite; panel c, total oxidative metabolites (APAP-CYS + APAP-NAC). In panel c, the mean difference of percentage of total oxidative metabolites excreted between the two conditions (4.48% vs. 0.51%) was statistically significant, 95% CI = 2.31–5.63%, p = 0.003. No APAP-GSH was detected in any urine sample (LOQ = 0.25 μM).
Fig. 2
Fig. 2
Twenty-four-hour urinary excretion of the parent drug, APAP (panel a), and its non-oxidative APAP metabolites (APAP-Gluc, panel b; and APAP-Sulf, panel c) as percent of the ingested APAP dose for 5 subjects in each of the 2 treatment groups. Dotted lines connect individual subjects to illustrate individual changes.
Fig. 3
Fig. 3
Serial plasma concentrations (mean ± SEM, N = 5) of oxidative APAP metabolites (free APAP-CYS, panel a; and APAP-NAC, panel b) in the two treatment groups. APAP-NAC was not detected in any sample in treatment B (LOQ = 0.025 μM). APAP-GSH was not detected in any plasma sample in either treatment (LOQ = 0.25 μM).
Fig. 4
Fig. 4
Serial plasma concentrations (mean ± SEM, N = 5) of parent drug, APAP (panel a), and its non-oxidative metabolites (APAP-Gluc, panel b; and APAP-Sulf, panel c) in the 2 treatment conditions.
See this image and copyright information in PMC

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