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The Modulating Effects of Endogenous Substances on Drug Metabolising Enzymes and Implications for Inter-Individual Variability and Quantitative Prediction

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The cytochrome P450 family of enzymes play an important role in the metabolism of drugs and other xenobiotics. While genotypic variation can contribute to the inter-individual variability in drug metabolism, individuals sharing the same genotype for an enzyme can still show considerable variability in drug metabolising capacity by that enzyme. It is well recognised that in some disease states (e.g. inflammation, infection, diabetes) or other physiological conditions (e.g. pregnancy), the clearance of drugs may significantly alter, possibly via modulation of drug metabolising enzymes by varying levels of endogenous substances. This review investigates the current knowledge on the modulating effects of various endogenous substances on DMEs in vitro and possible utility of available in vitro data for quantitative prediction of clinical outcome. It is postulated that understanding and estimating the inter-individual variability in DMEs within each population might be possible by application of in vitro in vivo extrapolation linked physiologically-based pharmacokinetic modelling. However, in vitro information for building such quantitative relationships is currently not abundant.
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Keywords: Cytochrome P450; IVIVE; PBPK; down-regulation or up-regulation of DMEs; endogenous substances; hormones; predicting clinical outcome

Document Type: Research Article

Publication date: July 1, 2014

More about this publication?
  • 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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