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In Vitro Techniques to Study Drug–Drug Interactions of Drug Metabolism: Cytochrome P450

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Enzyme- and Transporter-Based Drug-Drug Interactions

Abstract

Approaches are discussed for the generation and use of in vitro data on metabolic reversible inhibition, time-dependent inhibition and induction to make predictions of in vivo drug–drug interactions. The in vitro experimental conduct, choice of probe substrates appropriate for individual P450 enzymes and the importance of nonspecific binding within in vitro systems are discussed. In addition to the inhibitor/inducer properties, the importance of enzyme turnover and the victim drug properties (e.g. parallel elimination pathways and gut enzymes) for quantitative prediction via either of three interaction mechanisms are discussed. Contribution of multiple inhibitors (or metabolites) and/or consequences of a multiple inhibition mechanisms are addressed, as well as mechanisms by which false negatives and false positives may result. Finally, perspectives on future application and improvements of these prediction strategies are outlined.

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Authors and Affiliations

  1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PT, UK

    J. Brian Houston

  2. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK

    Aleksandra Galetin

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  1. Leslie Dan Fac. Pharmacy, University of Toronto, College Street 144, Toronto, M5S 3M2, Canada

    K. Sandy Pang

  2. Bristol-Myers Squibb Company, Princeton, 08543, U.S.A.

    A. David Rodrigues

  3. AstraZeneca UK, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom

    Raimund M. Peter

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Houston, J.B., Galetin, A. (2010). In Vitro Techniques to Study Drug–Drug Interactions of Drug Metabolism: Cytochrome P450. In: Pang , K., Rodrigues, A., Peter, R. (eds) Enzyme- and Transporter-Based Drug-Drug Interactions. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0840-7_7

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