title: Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.
abstract: Acetaminophen (paracetamol-APAP) is the most common 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 analyzed 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 at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (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.
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: Adb
authors: A
authors: Vliegenthart
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: R A
authors: RA
authors: Kimmitt
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: J H
authors: JH
authors: Seymour
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: N Z
authors: NZ
authors: Homer
authors: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors: J I
authors: JI
authors: Clarke
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: M
authors: M
authors: Eddleston
authors: Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors: A
authors: A
authors: Gray
authors: Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|King's College London, London, UK.
authors: D M
authors: DM
authors: Wood
authors: Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|King's College London, London, UK.
authors: P I
authors: PI
authors: Dargan
authors: Emergency Department, Aberdeen Royal Infirmary, Aberdeen, UK.
authors: J G
authors: JG
authors: Cooper
authors: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors: D J
authors: DJ
authors: Antoine
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: D J
authors: DJ
authors: Webb
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: S C
authors: SC
authors: Lewis
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: D N
authors: DN
authors: Bateman
authors: Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, UK.
authors: J W
authors: JW
authors: Dear
mesh_terms: D000082:Acetaminophen / Q000097:blood* / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000097:blood* / Q000633:toxicity*; D000932:Antiemetics / Q000009:adverse effects; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood*; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D062787:Drug Overdose / Q000378:metabolism / Q000628:therapy; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017294:Ondansetron / Q000009:adverse effects; D012372:ROC Curve; D015203:Reproducibility of Results; D066007:Toxicokinetics; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D000932:Antiemetics; D015415:Biomarkers; D016166:Free Radical Scavengers; D000082:Acetaminophen; D017294:Ondansetron; D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D000111:Acetylcysteine