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Research ArticleArticle

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Akiko Watanabe, Koichi Nakamura, Noriko Okudaira, Osamu Okazaki and Ken-ichi Sudo
Drug Metabolism and Disposition July 2007, 35 (7) 1232-1238; DOI: https://doi.org/10.1124/dmd.107.015016
Akiko Watanabe
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Koichi Nakamura
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Noriko Okudaira
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Osamu Okazaki
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Ken-ichi Sudo
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Abstract

The CYP3A family is a major drug metabolism enzyme in humans. Metabolism-based inhibition of CYP3A might cause clinically significant drug-drug interactions (DDIs). To assess the risk of DDIs caused by metabolism-based inhibition (MBI) of CYP3A, we established an automated single time- and concentration-dependent inhibition assay. To create a diagram to assess DDI risk of compounds in the early discovery stage, we classified 171 marketed drugs by the possibility of the occurrence of in vivo DDI caused by MBI from the relationship between the inactivation activity determined in the MBI screening, the therapeutic blood or plasma concentration, and the in vivo DDI information. This analysis revealed that the DDI risk depends on both the MBI potential and the blood concentration of a compound, and provided the criteria of the DDI risk. In the assay, three compounds (midazolam, nifedipine, and testosterone) were compared as CYP3A probe substrates. The results show that the evaluation for MBI does not depend on the probe substrates used in the assay. In addition, we established an automated assay to distinguish quasi-irreversible and irreversible binding to CYP3A in which the quasi-irreversible inhibitors such as diltiazem, verapamil, and nicardipine were dissociated from CYP3A by the addition of potassium ferricyanide, whereas the irreversible inhibitors such as clozapine, delavirdine, and mibefradil were not. It provides useful information related to chemical structures likely to cause MBI. By using these MBI assays supported by an extensive database of marketed compounds, a systematic MBI evaluation paradigm was established and has been incorporated into our drug discovery process.

Footnotes

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

  • doi:10.1124/dmd.107.015016.

  • ABBREVIATIONS: P450, cytochrome P450; MBI, metabolism-based inhibition; DDI, drug-drug interaction; HLM, human liver microsome; LC/MS, liquid chromatography/mass spectrometry.

    • Received January 30, 2007.
    • Accepted March 27, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (7)
Drug Metabolism and Disposition
Vol. 35, Issue 7
1 Jul 2007
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Research ArticleArticle

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Akiko Watanabe, Koichi Nakamura, Noriko Okudaira, Osamu Okazaki and Ken-ichi Sudo
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1232-1238; DOI: https://doi.org/10.1124/dmd.107.015016

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Research ArticleArticle

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Akiko Watanabe, Koichi Nakamura, Noriko Okudaira, Osamu Okazaki and Ken-ichi Sudo
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1232-1238; DOI: https://doi.org/10.1124/dmd.107.015016
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