Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury

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. Pla...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2017-04, Vol.101 (4), p.531-540
Main Authors: Vliegenthart, ADB, Kimmitt, RA, Seymour, JH, Homer, NZ, Clarke, JI, Eddleston, M, Gray, A, Wood, DM, Dargan, PI, Cooper, JG, Antoine, DJ, Webb, DJ, Lewis, SC, Bateman, DN, Dear, JW
Format: Article
Language:English
Subjects:
Acetaminophen - blood
Acetaminophen - toxicity
Acetylcysteine - pharmacology
Adult
Alanine Transaminase - metabolism
Analgesics, Non-Narcotic - blood
Analgesics, Non-Narcotic - toxicity
Antiemetics - adverse effects
Area Under Curve
Biomarkers - blood
Chemical and Drug Induced Liver Injury - blood
Cohort Studies
Cytochrome P-450 Enzyme System - metabolism
Drug Interactions
Drug Overdose - metabolism
Drug Overdose - therapy
Female
Free Radical Scavengers - pharmacology
Humans
Male
Middle Aged
Ondansetron - adverse effects
Reproducibility of Results
ROC Curve
Toxicokinetics
Young Adult
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Summary: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.
ISSN:0009-9236
1532-6535
DOI:10.1002/cpt.541