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Drug Metabolism and Disposition Fast Forward
First published on January 26, 2005; DOI: 10.1124/dmd.104.003236

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Received for publication December 10, 2004.
Revised January 20, 2005.
Accepted for publication January 21, 2005.

Metabolism-based Drug-Drug Interactions: What Determines Individual Variability in Cytochrome P450 Induction?

Cuyue Tang 1*, Jiunn H. Lin 2, Anthony Y.H. Lu 3

1 Merck Research Laboratories 2 Merck & Co. Inc 3 Retired

* Address correspondence to: E-mail: cuyue_tang{at}merck.com

Abstract

Individual variability in cytochrome P450 (P450) induction comprises an important component contributing to the difficulties in assessing and predicting metabolism-based drug-drug interactions in humans. In this commentary, we outline the major factors responsible for the individual variability in P450 induction, including variable transporter activity and metabolism of inducers in vivo, genetic variations of P450 genes and their regulatory regions, genetic variations of receptors and regulatory proteins required for induction, and different physiological and environmental elements. With a better understanding of the major determinants in P450 induction and a profile of the phenotypes of these determinants in each individual, it is believed that the individual variability in induction-mediated drug-drug interactions can be adequately evaluated.


Key words: CAR, cytochrome P450, drug-drug interactions, induction, p-glycoprotein, polymorphisms, PXR


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