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Research ArticleArticle

Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Hideo Takakusa, Hiroshi Masumoto, Hideo Yukinaga, Chie Makino, Shintaro Nakayama, Osamu Okazaki and Kenichi Sudo
Drug Metabolism and Disposition September 2008, 36 (9) 1770-1779; DOI: https://doi.org/10.1124/dmd.108.021725
Hideo Takakusa
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Hiroshi Masumoto
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Hideo Yukinaga
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Chie Makino
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Shintaro Nakayama
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Osamu Okazaki
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Kenichi Sudo
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Abstract

Bioactivation of a drug to a reactive metabolite and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including idiosyncratic drug toxicities (IDTs). For the interpretation of the covalent binding data in terms of risk assessment, the in vitro and in vivo covalent binding data of a variety of drugs associated with IDTs or not were determined. Most of the “problematic” drugs, including “withdrawn” and “warning” drugs, exhibit higher human liver microsome (HLM) in vitro covalent binding yields than the “safe” drugs. Although some of the problematic drugs that are known to undergo bioactivation other than cytochrome P450-mediated oxidation exhibited only trace levels of HLM covalent binding like safe drugs, a rat in vivo covalent binding study could assess the bioactivation of such drugs. Furthermore, the tissue distribution/retention of the drugs was also examined by rat autoradiography (ARG). The residual radioactivity in the liver observed at 72 or 168 h postdose was found to be well correlated with the rat in vivo covalent binding to liver proteins; thus, the in vivo covalent binding yields of the drugs could be extrapolated from the retention profiles observed by means of ARG. Long-term retention of radioactivity in the bone marrow was observed with some drugs associated with severe agranulocytosis, suggesting a spatial relationship between the toxicity profile and drug distribution/retention. Taken together, the covalent binding and tissue distribution/retention data of the various marketed drugs obtained in the present study should be quite informative for the interpretation of data in terms of risk assessment.

Footnotes

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

  • doi:10.1124/dmd.108.021725.

  • ABBREVIATIONS: IDT, idiosyncratic drug toxicity; NCE, new chemical entity; GSH, glutathione; ARG, autoradiography; HLM, human liver microsome; RLM, rat liver microsome; P450, cytochrome P450.

    • Received April 1, 2008.
    • Accepted May 27, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Research ArticleArticle

Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Hideo Takakusa, Hiroshi Masumoto, Hideo Yukinaga, Chie Makino, Shintaro Nakayama, Osamu Okazaki and Kenichi Sudo
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1770-1779; DOI: https://doi.org/10.1124/dmd.108.021725

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Research ArticleArticle

Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity

Hideo Takakusa, Hiroshi Masumoto, Hideo Yukinaga, Chie Makino, Shintaro Nakayama, Osamu Okazaki and Kenichi Sudo
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1770-1779; DOI: https://doi.org/10.1124/dmd.108.021725
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