Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

Raj Badhan, Jeffrey Penny, Aleksandra Galetin, J. Brian Houston

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte ( FG) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted FG values were within 20% of observed in vivo F G. The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. FG was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.
    Original languageEnglish
    Pages (from-to)2180-2197
    Number of pages17
    JournalJournal of Pharmaceutical Sciences
    Volume98
    Issue number6
    DOIs
    Publication statusPublished - Jun 2009

    Keywords

    • CYP3A4
    • Intestinal absorption
    • P-glycoprotein
    • Pharmacokinetics
    • Physiologically based pharmacokinetics

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