A metabolomic analysis of thiol response for standard and modified N‐acetyl cysteine treatment regimens in patients with acetaminophen overdose

N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patien...

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Bibliographic Details
Published in:Clinical and translational science Vol. 14; no. 4; pp. 1476 - 1489
Main Authors: Dear, James W, Ng, Mei Li, Bateman, D. Nicholas, Leroy Sivappiragasam, Pakkiri, Choi, Hyungwon, Khoo, Benjamin Bing Jie, Ibrahim, Baharudin, Drum, Chester Lee
Format: Journal Article
Language:English
Published: United States John Wiley & Sons, Inc 01.07.2021
John Wiley and Sons Inc
Wiley
Subjects:
Acetaminophen
Acetaminophen - pharmacokinetics
Acetaminophen - poisoning
Acetylcysteine
Acetylcysteine - administration & dosage
Adult
Alanine
Alanine transaminase
Analgesics
Antidotes - administration & dosage
Antioxidants
Biomarkers
Biomarkers - blood
Biomarkers - metabolism
Chemical and Drug Induced Liver Injury - blood
Chemical and Drug Induced Liver Injury - diagnosis
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - prevention & control
Clinical trials
Cysteine
Drug Administration Schedule
Drug Monitoring - methods
Drug Overdose - blood
Drug Overdose - drug therapy
Drug Overdose - etiology
Female
Humans
Infusions, Intravenous
Liquid chromatography
Liver
Male
Mass spectroscopy
Metabolism
Metabolites
Metabolomics
Middle Aged
Mitochondria
Nonsteroidal anti-inflammatory drugs
Overdose
Oxidation-Reduction - drug effects
Oxidative stress
Paracetamol
Patients
Plasma
Regulatory agencies
ROC Curve
Sulfhydryl Compounds - blood
Sulfhydryl Compounds - metabolism
United Kingdom > UK
Scotland
ISSN:1752-8054, 1752-8062, 1752-8062
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Description
Summary:N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h 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 h, and 20.25 h post‐start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post‐infusion. 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‐metabolites 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‐metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h 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‐induced ALI.
Bibliography:Funding information
James W. Dear and Mei Li Ng contributed equally to this work.
This study was generously supported by the Clinician Scientist Award (CSA) grant, National Medical Research Council of the Singapore Ministry of Health [CSAINV17nov12], and National Research Foundation, under its artificial intelligence (AI) Singapore Programme (AISG Award No: AISG‐GC‐2019‐002).
Correction added on 20 April, 2021, after first online publication: The author name Bing Jie Khoo has been corrected as Benjamin Bing Jie Khoo in the author byline.
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ISSN:1752-8054
1752-8062
1752-8062
DOI:10.1111/cts.13009