A Min Kang1,2, Angela Padilla-Jones3, Erik S Fisher3, Jephte Y Akakpo4, Hartmut Jaeschke4, Barry H Rumack5, Richard D Gerkin3, Steven C Curry6,3. 1. Division of Clinical Data Analytics and Decision Support, and Division of Medical Toxicology and Precision Medicine, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA. aaron.kang@bannerhealth.com. 2. Department of Medical Toxicology, Banner - University Medical Center Phoenix, 1012 E. Willetta St., Fl 2, Phoenix, AZ, 85006, USA. aaron.kang@bannerhealth.com. 3. Department of Medical Toxicology, Banner - University Medical Center Phoenix, 1012 E. Willetta St., Fl 2, Phoenix, AZ, 85006, USA. 4. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA. 5. Department of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA. 6. Division of Clinical Data Analytics and Decision Support, and Division of Medical Toxicology and Precision Medicine, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.
Abstract
INTRODUCTION:Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochromeP450 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.
RCT Entities:
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.
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