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Research ArticleArticle

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

Toru Usui, Masashi Mise, Takanori Hashizume, Masashi Yabuki and Setsuko Komuro
Drug Metabolism and Disposition December 2009, 37 (12) 2383-2392; DOI: https://doi.org/10.1124/dmd.109.028860
Toru Usui
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Masashi Mise
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Takanori Hashizume
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Masashi Yabuki
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Setsuko Komuro
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Abstract

Prediction of idiosyncratic drug-induced liver injury (DILI) is difficult, and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromolecules in the liver. The objective of this study was to clarify whether the risk of idiosyncratic DILI can be estimated by comparing in vitro covalent binding (CB) levels among 12 positive compounds (acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, and troglitazone) for DILI and 12 negative compounds (acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetine, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, and zolpidem). After incubation with human liver microsomes in the presence of NADPH, there was a large overlap in the distribution of CB amounts between the positive and negative groups. On addition of UDP-glucuronic acid (UDPGA) as a cofactor for glucuronidation, the CB levels of bromfenac and diclofenac were increased. With addition of nucleophilic glutathione (GSH), values for most compounds were decreased. However, separation of the two groups on the basis of CB could not be improved by UDPGA or GSH. Furthermore, CB with human hepatocytes also failed to discriminate positive from negative compounds. Therefore, the CB amount alone is not sufficient for risk assessment of DILI. In contrast, when the CB amount was multiplied by the maximum daily dose, which may reflect maximum hepatic exposure, the two groups did become discriminated. Taken together, our findings suggest that the combination of CB amount and daily dose can estimate the risk of idiosyncratic DILI.

Footnotes

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

    doi:10.1124/dmd.109.028860

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

  • IDR
    idiosyncratic drug reaction
    DILI
    drug-induced liver injury
    CB
    covalent binding
    P450
    cytochrome P450
    UDPGA
    UDP-glucuronic acid
    Cmax
    maximum plasma concentration
    UGT
    UDP-glucuronosyltransferase
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry.

    • Received June 9, 2009.
    • Accepted August 27, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (12)
Drug Metabolism and Disposition
Vol. 37, Issue 12
1 Dec 2009
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Research ArticleArticle

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

Toru Usui, Masashi Mise, Takanori Hashizume, Masashi Yabuki and Setsuko Komuro
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2383-2392; DOI: https://doi.org/10.1124/dmd.109.028860

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Research ArticleArticle

Evaluation of the Potential for Drug-Induced Liver Injury Based on in Vitro Covalent Binding to Human Liver Proteins

Toru Usui, Masashi Mise, Takanori Hashizume, Masashi Yabuki and Setsuko Komuro
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2383-2392; DOI: https://doi.org/10.1124/dmd.109.028860
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