Trial reportClinical pharmacology and therapeutics2026
Effects of Fomepizole on Acetaminophen Oxidative Metabolism: A Randomized, Crossover Study in Human Volunteers.
Trial report in Clinical pharmacology and therapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
Acetaminophen overdose can cause liver injury. Hepatotoxicity results from N-acetyl-p-benzoquinone imine (NAPQI), generated via cytochrome P450-2E1 (CYP2E1). Acetylcysteine is the mainstay of treatment, but efficacy may be reduced with delayed administration or large ingestions. Fomepizole, a CYP2E1 inhibitor, reduces NAPQI when co-administered with acetaminophen, but its clinical relevance remains uncertain. The objective was to evaluate the effect of fomepizole administered 2 hours after acetaminophen ingestion in immediate- and modified-release overdose. In a randomized crossover study simulating overdose, healthy volunteers received ~≈80 mg/kg of either immediate- or modified-release acetaminophen followed by intravenous fomepizole or placebo 2 hours later. Volunteers crossed over after 2 weeks. Urine and serum were collected over 24 hours to measure acetaminophen, non-toxic metabolites (APAP-Glu, APAP-Sul), and NAPQI metabolites (APAP-Mer, APAP-Cys). The primary outcome was the proportion of NAPQI metabolites in urine relative to total excreted compounds. Secondary outcomes included 24-hour AUCs for metabolites. Five crossover pairs were completed per formulation. Median 24-hour urinary recovery was 92% (IQR: 89-95%). Fomepizole significantly reduced the mean percentage of urinary NAPQI metabolites for both immediate-release (4.92% [SD: 0.97] vs. 1.72% [SD: 0.3], mean difference [fomepizole-control]: -3.20%, 95% CI: -4.45 to -1.95%, P = 0.0021) and modified release acetaminophen (5.62% [SD: 1.1] vs. 1.43% [SD: 0.3], mean difference [fomepizole-control]: -4.19%, 95% CI: -5.23 to -3.15%, P = 0.0004). Mean serum NAPQI metabolite AUCs were lower with fomepizole: 89.3 [SD: 11.1] vs. 32.5 [SD: 3.3] μmol/L*h (mean difference [fomepizole-control]: -56.8, 95% CI: -72.6 to -41.0, P =0.0006) for immediate-release, and 96.7 [SD: 15.2] vs. 27.2 [SD:7.2] μmol/L*h (mean difference [fomepizole-control]: -69.5, 95% CI:-84.6 to -54.4, P = 0.0002) for modified-release acetaminophen. Fomepizole, administered 2 hours after an acetaminophen overdose, reduced NAPQI formation by 60-70%, supporting further evaluation as an adjunct in overdoses where acetylcysteine may be insufficient.
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