Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury

Bastiaan Vliegenthart, Robert A. Kimmitt, JH Seymour, Natalie Homer, J I Clarke, Michael Eddleston, A. Gray, D M Wood, Paul I Dargan, J G Cooper, Daniel J Antoine, David Webb, Steff Lewis, D Nicholas Bateman, James Dear

Research output: Contribution to journalArticlepeer-review


Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that hospital presentation CYP-metabolites were more sensitive/specific for ALI than ALT activity and APAP concentration (optimal CYP-metabolite ROC-AUC:0.91 (95%CI 0.83-0.98). ALT ROC-AUC:0.67 (0.50-0.84). APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.
Original languageEnglish
Pages (from-to)531-540
JournalClinical Pharmacology & Therapeutics
Issue number4
Early online date22 Oct 2016
Publication statusPublished - 1 Apr 2017


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