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This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25\u00a0h standard or 12\u00a0h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12\u00a0h, and 20.25\u00a0h post\u2010start of NAC infusion. The results showed that the 12\u00a0h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12\u00a0h post\u2010infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP\u2010metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP\u2010metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12\u00a0h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP\u2010induced ALI.<\/jats:p>","DOI":"10.1111\/cts.13009","type":"journal-article","created":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T10:30:45Z","timestamp":1616236245000},"page":"1476-1489","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A metabolomic analysis of thiol response for standard and modified <i>N<\/i>\u2010acetyl cysteine treatment regimens in patients with acetaminophen overdose"],"prefix":"10.1111","volume":"14","author":[{"given":"James W","family":"Dear","sequence":"first","affiliation":[{"name":"Pharmacology, Toxicology, and Therapeutics Centre for Cardiovascular Science University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei Li","family":"Ng","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute National University Health System Singapore City Singapore"},{"name":"Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore City Singapore"},{"name":"Advanced Medical and Dental Institute Universiti Sains Malaysia Kepala Batas Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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