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

• Published in: Drug metabolism and disposition Vol. 37; no. 8; pp. 1779 - 1784
• Main Authors: JAMES, Laura P, LETZIG, Lynda, SIMPSON, Pippa M, CAPPARELLI, Edmund, ROBERTS, Dean W, HINSON, Jack A, DAVERN, Timothy J, LEE, William M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-08-2009
• Subjects: Acetaminophen - administration & dosage; Acetaminophen - analogs & derivatives; Acetaminophen - blood; Acetaminophen - pharmacokinetics; Acetaminophen - poisoning; Acetylcysteine - therapeutic use; Adult; Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - blood; Analgesics, Non-Narcotic - pharmacokinetics; Analgesics, Non-Narcotic - poisoning; Antidotes - therapeutic use; Bayes Theorem; Benzoquinones - metabolism; Biological and medical sciences; Biomarkers - blood; Biotransformation; Databases as Topic; Drug Overdose; Female; Gastroenterology. Liver. Pancreas. Abdomen; Half-Life; Humans; Imines - metabolism; Liver Failure, Acute - chemically induced; Liver Failure, Acute - drug therapy; Liver Failure, Acute - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Models, Biological; Models, Statistical; Nonlinear Dynamics; Other diseases. Semiology; Pharmacology. Drug treatments; Young Adult; Human; Acute; Antimigrainous agent; Overdosing; Hepatic disease; Protein; Liver failure; Paracetamol; Analgesic; Antipyretic; Digestive diseases; Adult; Pharmacokinetics; Molecular adduct; Adduct
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.108.026195

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.