“Massive” modified-release paracetamol overdose: fomepizole use and measured CYP metabolites

Introduction Modified-release paracetamol ingestions are associated with an increased risk of hepatotoxicity. Fomepizole, a CYP2E1 inhibitor, may reduce the formation of toxic metabolite. Despite its increasing use, no human metabolite data exist in overdose patients. We report two cases treated with adjunct fomepizole with metabolite analysis.Methods Samples were analysed for paracetamol and metabolites (APAP-Glu, APAP-Sul, APAP-Cys, and APAP-Mer) using LC–MS/MS. Urinary excretion was expressed as the percentage of total recovered (unchanged paracetamol plus metabolites).Results Case 1: A 19-year-old female ingested 111.7 g modified-release paracetamol and 2.4 g ibuprofen. From 6.5 h post-ingestion, she received high-dose acetylcysteine and fomepizole. Peak ALT = 76 U/L. A 24-h urine (7.5–31.5 h post-ingestion) recovered 38.6% of the ingested dose: 20.2% unchanged paracetamol, 49.7% APAP-Glu, 24.4% APAP-Sul, and 5.7% CYP-derived metabolites.Case 2: A 60-year-old female ingested 105.9 g paracetamol (immediate-release and modified-release). She received high-dose acetylcysteine and fomepizole from 22 h post-ingestion. Peak ALT = 1765 U/L, and INR = 3.6. A 24-h urine (22–46 h post-ingestion) recovered 18.3% of the dose: 8.0% unchanged paracetamol, 73.9% APAP-Glu, 14.0% APAP-Sul, and 4.1% CYP-derived metabolites.Discussion Adjunct fomepizole was associated with low urinary CYP-derived metabolites (~5%), within the therapeutic range (5%–10%) and lower than typically observed in overdose.Conclusion These findings provide metabolite evidence supporting reduced CYP2E1-mediated metabolism following fomepizole in paracetamol overdose.