Effects of Fomepizole on Acetaminophen Oxidative Metabolism: A Randomized, Crossover Study in Human Volunteers

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.