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Towards a Quantitative Framework for the Prediction of DDIs Arising from Cytochrome P450 Induction

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Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro data to predict the in vivo consequences of enzyme inhibition, less attention has been given to the quantitative impact of enzyme induction as a mechanism of drug-drug interaction (DDI) and as a component of compound selection and early drug development. We discuss current approaches in the context of a mechanistic framework for the prediction of the extent and time-course of enzyme induction in vivo based on in vitro experimentation. Factors influencing the extent of DDI due to CYP induction are summarised, and areas deficient in information that would allow more accurate prediction within target populations are highlighted.





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Keywords: CYP-enzyme induction; drug-drug interactions; enzyme turn-over; in vitro - in vivo extrapolation; modelling and simulation; pharmacokinetics; quantitative pharmacology

Document Type: Research Article

Publication date: 01 May 2009

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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