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Review ArticleReview Article

A Critical Analysis of the Interplay between Cytochrome P450 3A and P-Glycoprotein: Recent Insights from Knockout and Transgenic Mice

Robert A. B. van Waterschoot and Alfred H. Schinkel
Emily E. Scott, ASSOCIATE EDITOR
Pharmacological Reviews June 2011, 63 (2) 390-410; DOI: https://doi.org/10.1124/pr.110.002584
Robert A. B. van Waterschoot
Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Alfred H. Schinkel
Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
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Emily E. Scott
Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
Roles: ASSOCIATE EDITOR
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Abstract

CYP3A is one of the most important drug-metabolizing enzymes, determining the first-pass metabolism, oral bioavailability, and elimination of many drugs. It is also an important determinant of variable drug exposure and is involved in many drug-drug interactions. Recent studies with CYP3A knockout and transgenic mice have yielded a number of key insights that are important to consider during drug discovery and development. For instance, studies with tissue-specific CYP3A-transgenic mice have highlighted the importance of intestinal CYP3A-dependent metabolism. They also revealed that intestinal CYP3A plays an important role in the regulation of various drug-handling systems in the liver. Intestinal CYP3A activity can thus have far-reaching pharmacological effects. Besides CYP3A, the active drug efflux transporter P-glycoprotein also has a strong effect on the pharmacokinetics of numerous drugs. CYP3A and P-glycoprotein have an extensive overlap in their substrate spectrum. It has been hypothesized that for many drugs, the combined activity of CYP3A and P-glycoprotein makes for efficient intestinal first-pass metabolism of orally administered drugs as a result of a potentially synergistic collaboration. However, there is only limited in vitro and in vivo evidence for this hypothesis. There has also been some confusion in the field about what synergy actually means in this case. Our recent studies with Cyp3a/P-glycoprotein combination knockout mice have provided further insights into the CYP3A-P-glycoprotein interplay. We here present our view of the status of the synergy hypothesis and an attempt to clarify the existing confusion about synergy. We hope that this will facilitate further critical testing of the hypothesis and improve communication among researchers. Above all, the recent findings and insights into the interplay between CYP3A and P-glycoprotein may have implications for improving oral drug bioavailability and reducing adverse side effects.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.002584.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (2)
Pharmacological Reviews
Vol. 63, Issue 2
1 Jun 2011
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Review ArticleReview Article

A Critical Analysis of the Interplay between Cytochrome P450 3A and P-Glycoprotein: Recent Insights from Knockout and Transgenic Mice

Robert A. B. van Waterschoot and Alfred H. Schinkel
Pharmacological Reviews June 1, 2011, 63 (2) 390-410; DOI: https://doi.org/10.1124/pr.110.002584

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Review ArticleReview Article

A Critical Analysis of the Interplay between Cytochrome P450 3A and P-Glycoprotein: Recent Insights from Knockout and Transgenic Mice

Robert A. B. van Waterschoot and Alfred H. Schinkel
Pharmacological Reviews June 1, 2011, 63 (2) 390-410; DOI: https://doi.org/10.1124/pr.110.002584
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  • Article
    • Abstract
    • I. Introduction
    • II. Importance of CYP3A in Drug-Drug and Drug-Food Interactions
    • III. Insights from Cyp3a Knockout Mice
    • IV. Insights from Tissue-Specific CYP3A4-Transgenic Mouse Models
    • V. Interplay between CYP3A and P-Glycoprotein
    • VI. Novel Mouse Models to Study the In Vivo Interplay between CYP3A and P-glycoprotein
    • VII. Perspectives and Concluding Remarks
    • Acknowledgments
    • Authorship Contributions
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