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Research ArticleArticle

Effect of CYP3A5 Expression on the Inhibition of CYP3A-Catalyzed Drug Metabolism: Impact on Modeling CYP3A-Mediated Drug-Drug Interactions

Yoshiyuki Shirasaka, Shu-Ying Chang, Mary F. Grubb, Chi-Chi Peng, Kenneth E. Thummel, Nina Isoherranen and A. David Rodrigues
Drug Metabolism and Disposition August 2013, 41 (8) 1566-1574; DOI: https://doi.org/10.1124/dmd.112.049940
Yoshiyuki Shirasaka
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Shu-Ying Chang
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Mary F. Grubb
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Chi-Chi Peng
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Kenneth E. Thummel
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Nina Isoherranen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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A. David Rodrigues
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (Y.S., C.-C.P., K.E.T., N.I.); and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., M.F.G., A.D.R.)
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Abstract

The purpose of this study was to determine the impact of CYP3A5 expression on inhibitory potency (Ki or IC50 values) of CYP3A inhibitors, using recombinant CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) and CYP3A5 genotyped human liver microsomes (HLMs). IC50 ratios between rCYP3A4 and rCYP3A5 (rCYP3A5/rCYP3A4) of ketoconazole (KTZ) and itraconazole (ITZ) were 8.5 and 8.8 for midazolam (MDZ), 4.7 and 9.1 for testosterone (TST), 1.3 and 2.8 for terfenadine, and 0.6 and 1.7 for vincristine, respectively, suggesting substrate- and inhibitor-dependent selectivity of the two azoles. Due to the difference in the IC50 values for CYP3A4 and CYP3A5, nonconcordant expression of CYP3A4 and CYP3A5 protein can significantly affect the observed magnitude of CYP3A-mediated drug-drug interactions in humans. Indeed, the IC50 values of KTZ and ITZ for CYP3A-catalyzed MDZ and TST metabolism were significantly higher in HLMs with CYP3A5*1/*1 and CYP3A5*1/*3 genotypes than in HLMs with the CYP3A5*3/*3 genotype, showing CYP3A5 expression–dependent IC50 values. Moreover, when IC50 values of KTZ and ITZ for different HLMs were kinetically simulated based on CYP3A5 expression level and enzyme-specific IC50 values, a good correlation between the simulated and the experimentally measured IC50 values was observed. Further simulation analysis revealed that both the Ki ratio (for inhibitors) and Vmax/Km ratio (for substrates) between CYP3A4 and CYP3A5 were major factors for CYP3A5 expression–dependent IC50 values. In conclusion, the present study demonstrates that CYP3A5 genotype and expression level have a significant impact on inhibitory potency for CYP3A-catalyzed drug metabolism, but that the magnitude of its effect is inhibitor-substrate pair specific.

Footnotes

    • Received November 2, 2012.
    • Accepted May 30, 2013.
  • This work was supported in part by a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science [Research Project Number H23-694]; and the National Institutes of Health National Institute of General Medical Sciences [Grant P01 GM32165].

  • dx.doi.org/10.1124/dmd.112.049940.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

Impact of CYP3A5 Expression on CYP3A-Mediated DDIs

Yoshiyuki Shirasaka, Shu-Ying Chang, Mary F. Grubb, Chi-Chi Peng, Kenneth E. Thummel, Nina Isoherranen and A. David Rodrigues
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1566-1574; DOI: https://doi.org/10.1124/dmd.112.049940

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Research ArticleArticle

Impact of CYP3A5 Expression on CYP3A-Mediated DDIs

Yoshiyuki Shirasaka, Shu-Ying Chang, Mary F. Grubb, Chi-Chi Peng, Kenneth E. Thummel, Nina Isoherranen and A. David Rodrigues
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1566-1574; DOI: https://doi.org/10.1124/dmd.112.049940
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