Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure
Open accessAbstract
Acetaminophen (APAP)-induced liver toxicity occurs with formation of APAP-protein adducts. These adducts are formed by hepatic metabolism of APAP to N-acetyl-p-benzoquinone imine, which covalently binds to hepatic proteins as 3-(cystein-S-yl)-APAP adducts. Adducts are released into blood during hepatocyte lysis. We previously showed that adducts could be quantified by high-performance liquid chromatography with electrochemical detection following proteolytic hydrolysis, and that the concentration of adducts in serum of overdose patients correlated with toxicity. The following study examined the pharmacokinetic profile and clinical associations of adducts in 53 adults with acute APAP overdose resulting in acute liver failure. A population pharmacokinetic analysis using nonlinear mixed effects (statistical regression type) models was conducted; individual empiric Bayesian estimates were determined for the elimination rate constant and elimination half-life. Correlations between clinical and laboratory data were examined relative to adduct concentrations using nonparametric statistical approaches. Peak concentrations of APAP-protein adducts correlated with peak aminotransferase concentrations (r = 0.779) in adults with APAP-related acute liver failure. Adducts did not correlate with bilirubin, creatinine, and APAP concentration at admission, international normalized ratio for prothrombin time, or reported APAP dose. After N-acetylcysteine therapy, adducts exhibited first-order disappearance. The mean elimination rate constant and elimination half-life were 0.42 +/- 0.09 days(-1) and 1.72 +/- 0.34 days, respectively, and estimates from the population model were in strong agreement with these data. Adducts were detected in some patient samples 12 days post-ingestion. The persistence and specificity of APAP-protein adducts as correlates of toxicity support their use as specific biomarkers of APAP toxicity in patients with acute liver injury.
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Paracetamol-protein adducts have been shown to be marginally superior to traditional biomarkers at predicting acute liver injury and can diagnose paracetamol-induced hepatotoxicity in the absence of a history of ingestion.
“Paracetamol-protein adducts have been shown to be marginally superior to traditional biomarkers at predicting acute liver injury and can diagnose paracetamol-induced hepatotoxicity in the absence of a history of ingestion [38,82,92,93].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [93]
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- Authors
- James, L. P., Letzig, L., Simpson, P. M., Capparelli, E., Roberts, D. W., Hinson, J. A., Davern, T. J., & Lee, W. M.
- Affiliations
- Arkansas Children's Hospital (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 37
- Issue
- 8
- Pages
- 1779-1784
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC2712440
- OpenAlex
- W2167322494
- Cited by
- 175
- References
- 25
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 15 · 2022: 7 · 2021: 4 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 18 · 2015: 19 · 2014: 11 · 2013: 17 · 2012: 7
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 58639, DK06799)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- paracetamol, acute liver failure, acetaminophen overdose, pharmacokinetics, N-acetyl-p-benzoquinone imine, N-acetylcysteine, transaminases, elimination half-life, population pharmacokinetic model
- MeSH terms
- Acetaminophen, Acetylcysteine, Adult, Antidotes, Bayes Theorem, Biotransformation, Female, Half-Life, Humans, Imines, Male, Metabolic Clearance Rate, Middle Aged, Models, Biological, Models, Statistical, Biomarkers, Benzoquinones, Liver Failure, Acute, Nonlinear Dynamics, Analgesics, Non-Narcotic, Databases as Topic, Young Adult, Drug Overdose
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