{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:50:42Z","timestamp":1786114242479,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Acetaminophen overdose can cause liver injury. Hepatotoxicity results from\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl\u2010\n                    <jats:italic>p<\/jats:italic>\n                    \u2010benzoquinone imine (NAPQI), generated via cytochrome P450\u20102E1 (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\u2010administered 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\u2010 and modified\u2010release overdose. In a randomized crossover study simulating overdose, healthy volunteers received ~\u224880\u2009mg\/kg of either immediate\u2010 or modified\u2010release acetaminophen followed by intravenous fomepizole or placebo 2 hours later. Volunteers crossed over after 2\u2009weeks. Urine and serum were collected over 24 hours to measure acetaminophen, non\u2010toxic metabolites (APAP\u2010Glu, APAP\u2010Sul), and NAPQI metabolites (APAP\u2010Mer, APAP\u2010Cys). The primary outcome was the proportion of NAPQI metabolites in urine relative to total excreted compounds. Secondary outcomes included 24\u2010hour AUCs for metabolites. Five crossover pairs were completed per formulation. Median 24\u2010hour urinary recovery was 92% (IQR: 89\u201395%). Fomepizole significantly reduced the mean percentage of urinary NAPQI metabolites for both immediate\u2010release (4.92% [SD: 0.97] vs. 1.72% [SD: 0.3], mean difference [fomepizole\u2013control]: \u20103.20%, 95% CI: \u22124.45 to \u22121.95%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0021) and modified release acetaminophen (5.62% [SD: 1.1] vs. 1.43% [SD: 0.3], mean difference [fomepizole\u2013control]: \u22124.19%, 95% CI: \u22125.23 to \u22123.15%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0004). Mean serum NAPQI metabolite AUCs were lower with fomepizole: 89.3 [SD: 11.1]\u00a0vs. 32.5 [SD: 3.3]\u2009\u03bcmol\/L*h (mean difference [fomepizole\u2013control]: \u221256.8, 95% CI: \u221272.6 to \u221241.0,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=0.0006) for immediate\u2010release, and 96.7 [SD: 15.2]\u00a0vs. 27.2 [SD:7.2]\u2009\u03bcmol\/L*h (mean difference [fomepizole\u2013control]: \u221269.5, 95% CI:\u201384.6 to \u221254.4,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0002) for modified\u2010release acetaminophen. Fomepizole, administered 2 hours after an acetaminophen overdose, reduced NAPQI formation by 60\u201370%, supporting further evaluation as an adjunct in overdoses where acetylcysteine may be insufficient.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70379","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:49:04Z","timestamp":1784029744000},"page":"795-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Fomepizole on Acetaminophen Oxidative Metabolism: A Randomized, Crossover Study in Human Volunteers"],"prefix":"10.1002","volume":"120","author":[{"given":"Sidharth","family":"Anand","sequence":"first","affiliation":[{"name":"Faculty of Medicine The University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-4711","authenticated-orcid":false,"given":"Nicholas A.","family":"Buckley","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health The University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Stathakis","sequence":"additional","affiliation":[{"name":"NSW Health Pathology, Prince of Wales Hospital  Randwick New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine University of Arkansas for Medical Sciences  Little Rock Arkansas USA"},{"name":"Acetaminophen Toxicity Diagnostics, LLC  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Parker","sequence":"additional","affiliation":[{"name":"Acetaminophen Toxicity Diagnostics, LLC  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0401-0463","authenticated-orcid":false,"given":"Mitchell R.","family":"McGill","sequence":"additional","affiliation":[{"name":"Acetaminophen Toxicity Diagnostics, LLC  Little Rock Arkansas USA"},{"name":"Department of Environmental Health Sciences, Fay W. 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