Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure
Open Access
- 13 May 2009
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 37 (8), 1779-1784
- https://doi.org/10.1124/dmd.108.026195
Abstract
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 postingestion. 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.Keywords
This publication has 23 references indexed in Scilit:
- Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen OverdoseClinical Pharmacology & Therapeutics, 2008
- False positive acetaminophen concentrations in patients with liver injuryClinica Chimica Acta; International Journal of Clinical Chemistry, 2008
- CYP2E1Drug Metabolism and Disposition, 2006
- Indeterminate acute liver failure: A riddle wrapped in a mystery inside an enigmaHepatology, 2006
- Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective studyHepatology, 2005
- In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal MucosaMolecular Pharmacology, 2004
- Mechanism of paracetamol toxicityThe Lancet, 1990
- Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen OverdoseNew England Journal of Medicine, 1988
- Structural characterization of the major covalent adduct formed in vitro between acetaminophen and bovine serum albuminChemico-Biological Interactions, 1985
- Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatmentArchives of Internal Medicine, 1981