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Research ArticleArticle

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Lydia M. M. Vermeer, Caleb D. Isringhausen, Brian W. Ogilvie and David B. Buckley
Drug Metabolism and Disposition March 2016, 44 (3) 453-459; DOI: https://doi.org/10.1124/dmd.115.067744
Lydia M. M. Vermeer
Sekisui XenoTech, LLC Kansas City, Kansas
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Caleb D. Isringhausen
Sekisui XenoTech, LLC Kansas City, Kansas
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Brian W. Ogilvie
Sekisui XenoTech, LLC Kansas City, Kansas
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David B. Buckley
Sekisui XenoTech, LLC Kansas City, Kansas
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Abstract

Ketoconazole is a potent CYP3A4/5 inhibitor and, until recently, recommended by the Food and Drug Administration (FDA) and the European Medicines Agency as a strong CYP3A4/5 inhibitor in clinical drug-drug interaction (DDI) studies. Ketoconazole sporadically causes liver injury or adrenal insufficiency. Because of this, the FDA and European Medicines Agency recommended suspension of ketoconazole use in DDI studies in 2013. The FDA specifically recommended use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors in clinical DDI studies, but many investigators have also used ritonavir as an alternative. Although the effects of these clinical CYP3A4/5 inhibitors on other CYPs are largely established, reports on the effects on the broad range of drug transporter activities are sparse. In this study, the inhibitory effects of ketoconazole, clarithromycin, ritonavir, and itraconazole (and its CYP3A4-inhibitory metabolites, hydroxy-, keto-, and N-desalkyl itraconazole) toward 13 drug transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3, and BSEP) were systematically assessed in transporter-expressing HEK-293 cell lines or membrane vesicles. In vitro findings were translated into clinical context with the basic static model approaches outlined by the FDA in its 2012 draft guidance on DDIs. The results indicate that, like ketoconazole, the alternative clinical CYP3A4/5 inhibitors ritonavir, clarithromycin, and itraconazole each have unique transporter inhibition profiles. None of the alternatives to ketoconazole provided a clean inhibition profile toward the 13 drug transporters evaluated. The results provide guidance for the selection of clinical CYP3A4/5 inhibitors when transporters are potentially involved in a victim drug’s pharmacokinetics.

Footnotes

    • Received October 8, 2015.
    • Accepted December 11, 2015.
  • ↵1 L.M.M.V. and C.D.I. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.115.067744.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters
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Research ArticleArticle

Effect of Clinical CYP3A4/5 Inhibitors on Drug Transporters

Lydia M. M. Vermeer, Caleb D. Isringhausen, Brian W. Ogilvie and David B. Buckley
Drug Metabolism and Disposition March 1, 2016, 44 (3) 453-459; DOI: https://doi.org/10.1124/dmd.115.067744

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Research ArticleArticle

Effect of Clinical CYP3A4/5 Inhibitors on Drug Transporters

Lydia M. M. Vermeer, Caleb D. Isringhausen, Brian W. Ogilvie and David B. Buckley
Drug Metabolism and Disposition March 1, 2016, 44 (3) 453-459; DOI: https://doi.org/10.1124/dmd.115.067744
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