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Inactivation of Human Cytochrome P450 Enzymes and Drug–Drug Interactions

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Enzyme- and Transporter-Based Drug-Drug Interactions

Abstract

Inactivation of human P450 enzymes represents an important mechanism of drug–drug interactions (DDIs). Inactivators are distinct from other inhibitors in that the affected enzyme is responsible for bioactivating an otherwise inert drug into an intermediate that can irreversibly damage the enzyme, and recovery of activity in vivo requires the biosynthesis of new enzyme. Whether a new drug will be a mechanism-based inactivator depends on the identity of chemical substituents present in the substrate and their metabolism by the P450 enzyme. Experimental approaches used to define new drugs as possible time-dependent inhibitors and mechanism-based inactivators are described. Finally, it has been demonstrated that inactivation kinetic parameters generated in vitro can be used to predict DDI. The methods used to do this are described along with existing uncertainties in the input parameters needed for accurate predictions.

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Authors and Affiliations

  1. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Inc., Global Research & Development, Groton, CT, USA

    R. Scott Obach, Odette A. Fahmi & Robert L. Walsky

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  1. R. Scott Obach
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  2. Odette A. Fahmi
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  3. Robert L. Walsky
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Correspondence to R. Scott Obach .

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Editors and Affiliations

  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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Obach, R.S., Fahmi, O.A., Walsky, R.L. (2010). Inactivation of Human Cytochrome P450 Enzymes and Drug–Drug Interactions. 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_19

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