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Research ArticleToxicology

An Analysis of N-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Jeffrey L. Woodhead, Brett A. Howell, Yuching Yang, Alison H. Harrill, Harvey J. Clewell III, Melvin E. Andersen, Scott Q. Siler and Paul B. Watkins
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 529-540; DOI: https://doi.org/10.1124/jpet.112.192930
Jeffrey L. Woodhead
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Brett A. Howell
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Yuching Yang
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Alison H. Harrill
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Harvey J. Clewell III
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Melvin E. Andersen
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Scott Q. Siler
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Paul B. Watkins
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Abstract

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. Vmax for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

Footnotes

  • This research was supported by the DILI-sim Initiative of The Hamner Institutes for Health Sciences.

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

    http://dx.doi.org/10.1124/jpet.112.192930.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    APAP
    acetaminophen
    NAPQI
    N-acetyl-p-benzoquinone imine
    GSH
    glutathione
    NAC
    N-acetylcysteine
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    SimPops
    simulated sample population
    RNS-ROS
    reactive nitrogen species-reactive oxygen species
    INR
    international normalized ratio.

  • Received March 26, 2012.
  • Accepted May 3, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleToxicology

NAC Treatment Analysis Using a Systems Model of the Liver

Jeffrey L. Woodhead, Brett A. Howell, Yuching Yang, Alison H. Harrill, Harvey J. Clewell, Melvin E. Andersen, Scott Q. Siler and Paul B. Watkins
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 529-540; DOI: https://doi.org/10.1124/jpet.112.192930

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Research ArticleToxicology

NAC Treatment Analysis Using a Systems Model of the Liver

Jeffrey L. Woodhead, Brett A. Howell, Yuching Yang, Alison H. Harrill, Harvey J. Clewell, Melvin E. Andersen, Scott Q. Siler and Paul B. Watkins
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 529-540; DOI: https://doi.org/10.1124/jpet.112.192930
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