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Research ArticleArticle

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Robert S. Foti, Dan A. Rock, Larry C. Wienkers and Jan L. Wahlstrom
Drug Metabolism and Disposition June 2010, 38 (6) 981-987; DOI: https://doi.org/10.1124/dmd.110.032094
Robert S. Foti
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Dan A. Rock
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Larry C. Wienkers
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Jan L. Wahlstrom
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Abstract

Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine, and testosterone. However, the design of clinical CYP3A4 DDI studies may be confounded for cases such as 1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), with which testosterone is predicted to exhibit a clinically relevant DDI whereas midazolam and felodipine/nifedipine are not. To develop an appropriate path forward for such clinical DDI studies, the inhibition potency of 20 known inhibitors of CYP3A4 were measured in vitro using 8 clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine, and sildenafil; and simvastatin, budesonide, and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil, and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil, and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, Simcyp was used to predict the in vivo magnitude of CYP3A4 DDIs caused by AMG 458 using midazolam, sildenafil, simvastatin, and testosterone as probe substrates.

Footnotes

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

    doi:10.1124/dmd.110.032094.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    DDI
    drug-drug interaction
    AMG 458
    1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
    HPLC
    high-performance liquid chromatography
    DMSO
    dimethyl sulfoxide
    MS/MS
    tandem mass spectrometry.

  • Received January 6, 2010.
  • Accepted March 4, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (6)
Drug Metabolism and Disposition
Vol. 38, Issue 6
1 Jun 2010
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Research ArticleArticle

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Robert S. Foti, Dan A. Rock, Larry C. Wienkers and Jan L. Wahlstrom
Drug Metabolism and Disposition June 1, 2010, 38 (6) 981-987; DOI: https://doi.org/10.1124/dmd.110.032094

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Research ArticleArticle

Selection of Alternative CYP3A4 Probe Substrates for Clinical Drug Interaction Studies Using In Vitro Data and In Vivo Simulation

Robert S. Foti, Dan A. Rock, Larry C. Wienkers and Jan L. Wahlstrom
Drug Metabolism and Disposition June 1, 2010, 38 (6) 981-987; DOI: https://doi.org/10.1124/dmd.110.032094
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