Received for publication January 8, 2009.
Revised May 5, 2009.
Accepted for publication May 6, 2009.

Pharmacokinetics of Acetaminophen Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure

Abstract

Acetaminophen-induced liver toxicity occurs with formation of acetaminophen-protein adducts. These adducts are formed by hepatic metabolism of acetaminophen to N-acetyl-p-benzoquinone imine which covalently binds to hepatic proteins as 3-(cystein-S-yl)acetaminophen adducts. Adducts are released into blood during hepatocyte lysis. We previously showed that adducts could be quantified by HPLC 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 acetaminophen 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 non-parametric statistical approaches. Peak concentrations of acetaminophen protein adducts correlated with peak aminotransferase concentrations (R=0.779) in adults with acetaminophen related acute liver failure. Adducts did not correlate with bilirubin, creatinine, acetaminophen concentration at admission, international normalized ratio for prothrombin time, or reported acetaminophen dose. Following 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 acetaminophen protein adducts as correlates of toxicity support their utilization as specific biomarkers of acetaminophen toxicity in patients with acute liver injury.

Key words: clinical pharmacology, drug toxicity, drug-induced hepatotoxicity, hepatotoxicity, HPLC, human pharmacokinetics, liver injury, liver toxicity, toxicity, toxicokinetics