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

  • A. Min KangEmail author
  • Angela Padilla-Jones
  • Erik S. Fisher
  • Jephte Y. Akakpo
  • Hartmut Jaeschke
  • Barry H. Rumack
  • Richard D. Gerkin
  • Steven C. Curry
Original Article

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

Acetaminophen toxicity 4-Methylpyrazole Hepatotoxicity Overdose CYP2E1 

Notes

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

None.

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Copyright information

© American College of Medical Toxicology 2019

Authors and Affiliations

  1. 1.Division of Clinical Data Analytics and Decision Support, and Division of Medical Toxicology and Precision Medicine, Department of MedicineUniversity of Arizona College of Medicine – PhoenixPhoenixUSA
  2. 2.Department of Medical ToxicologyBanner – University Medical Center PhoenixPhoenixUSA
  3. 3.Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityUSA
  4. 4.Department of Emergency Medicine, Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA

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