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Research ArticleArticle

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

Laura P. James, Lynda Letzig, Pippa M. Simpson, Edmund Capparelli, Dean W. Roberts, Jack A. Hinson, Timothy J. Davern and William M. Lee
Drug Metabolism and Disposition August 2009, 37 (8) 1779-1784; DOI: https://doi.org/10.1124/dmd.108.026195
Laura P. James
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Lynda Letzig
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Pippa M. Simpson
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Edmund Capparelli
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Dean W. Roberts
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Jack A. Hinson
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Timothy J. Davern
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William M. Lee
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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.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK06799, DK58639].

  • Parts of this work were previously presented as follows: James LP, Simpson PM, Letzig L, Kearns GL, and Hinson JA (2007) Examination of acetaminophen protein adducts (APAP-CYS) in children and adolescents with acetaminophen overdose. Annual American Society for Clinical Pharmacology and Therapeutics Meeting; 2007 Mar 22; San Diego, CA. American Society for Clinical Pharmacology and Therapeutics, Washington, DC.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.026195.

  • ABBREVIATIONS: APAP, acetaminophen; ALF, acute liver failure; INR, international normalized ratio for prothrombin time; NAC, N-acetylcysteine; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

    • Accepted May 6, 2009.
    • Received December 17, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
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Research ArticleArticle

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

Laura P. James, Lynda Letzig, Pippa M. Simpson, Edmund Capparelli, Dean W. Roberts, Jack A. Hinson, Timothy J. Davern and William M. Lee
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1779-1784; DOI: https://doi.org/10.1124/dmd.108.026195

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Research ArticleArticle

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

Laura P. James, Lynda Letzig, Pippa M. Simpson, Edmund Capparelli, Dean W. Roberts, Jack A. Hinson, Timothy J. Davern and William M. Lee
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1779-1784; DOI: https://doi.org/10.1124/dmd.108.026195
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