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

doi:10.1002/cpt.541

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

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Abstract / Description of output

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 language	English
Pages (from-to)	531-540
Journal	Clinical Pharmacology & Therapeutics
Volume	101
Issue number	4
Early online date	22 Oct 2016
DOIs	https://doi.org/10.1002/cpt.541
Publication status	Published - 1 Apr 2017

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10.1002/cpt.541

Vliegenthart et al_CPT_V4
This is the Authors Accepted Manuscript as accepted by Clinical Pharmacology and Therapeutics on 18/10/16
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Development of urinary exosomes as biomarkers of drug-induced kidney injury
Dear, J.
UK central government bodies/local authorities, health and hospital authorities
1/10/13 → 30/09/16
Project: Research

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Vliegenthart, B., Kimmitt, R. A., Seymour, JH., Homer, N., Clarke, J. I., Eddleston, M., Gray, A., Wood, D. M., Dargan, P. I., Cooper, J. G., Antoine, D. J., Webb, D., Lewis, S., Bateman, D. N., & Dear, J. (2017). Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury. Clinical Pharmacology & Therapeutics, 101(4), 531-540. https://doi.org/10.1002/cpt.541

@article{13543b5b925448a9ada44f1aeb76afc6,

title = "Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury",

abstract = "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.",

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

note = "Acknowledgements Author ADBV was supported by an NC3Rs PhD Studentship (NC/K001485/1). Author JWD acknowledges the support of NHS Research Scotland (NRS) through NHS Lothian and a BHF Centre of Research Excellence Award. Conflict of Interest/Disclosure: The authors have no conflicts of interest to disclose. Author Contributions: JWD and ADBV wrote manuscript, ADBV, RAK, JHS, NZH, JIC performed research, ME, AG, DMW, PID and JGC recruited patients, JWD, DJA, DJW and DNB designed and reviewed research and SCL performed statistical analysis. ",

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doi = "10.1002/cpt.541",

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Vliegenthart, B, Kimmitt, RA, Seymour, JH, Homer, N, Clarke, JI, Eddleston, M, Gray, A, Wood, DM, Dargan, PI, Cooper, JG, Antoine, DJ, Webb, D , Lewis, S, Bateman, DN & Dear, J 2017, 'Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury', Clinical Pharmacology & Therapeutics, vol. 101, no. 4, pp. 531-540. https://doi.org/10.1002/cpt.541

TY - JOUR

T1 - Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury

AU - Vliegenthart, Bastiaan

AU - Kimmitt, Robert A.

AU - Seymour, JH

AU - Homer, Natalie

AU - Clarke, J I

AU - Eddleston, Michael

AU - Gray, A.

AU - Wood, D M

AU - Dargan, Paul I

AU - Cooper, J G

AU - Antoine, Daniel J

AU - Webb, David

AU - Lewis, Steff

AU - Bateman, D Nicholas

AU - Dear, James

N1 - Acknowledgements Author ADBV was supported by an NC3Rs PhD Studentship (NC/K001485/1). Author JWD acknowledges the support of NHS Research Scotland (NRS) through NHS Lothian and a BHF Centre of Research Excellence Award. Conflict of Interest/Disclosure: The authors have no conflicts of interest to disclose. Author Contributions: JWD and ADBV wrote manuscript, ADBV, RAK, JHS, NZH, JIC performed research, ME, AG, DMW, PID and JGC recruited patients, JWD, DJA, DJW and DNB designed and reviewed research and SCL performed statistical analysis.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

U2 - 10.1002/cpt.541

DO - 10.1002/cpt.541

M3 - Article

C2 - 27770431

SN - 0009-9236

VL - 101

SP - 531

EP - 540

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

IS - 4

ER -

Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury

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Development of urinary exosomes as biomarkers of drug-induced kidney injury

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