Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

Colin J. Henderson, Lesley A. McLaughlin, Maria Osuna-Cabello, Malcolm Taylor, Ian Gilbert, Aileen W. McLaren, C. Roland Wolf (Lead / Corresponding author)

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    Abstract

    The relative contribution of hepatic compared with intestinal oxidative metabolism is a crucial factor in drug oral bioavailability and therapeutic efficacy. Oxidative metabolism is mediated by the cytochrome P450 mono-oxygenase system to which cytochrome P450 reductase (POR) is the essential electron donor. In order to study the relative importance of these pathways in drug disposition, we have generated a novel mouse line where Cre recombinase is driven off the endogenous Cyp1a1 gene promoter; this line was then crossed on to a floxed POR mouse. A 40 mg/kg dose of the Cyp1a1 inducer 3-methylcholanthrene (3MC) eliminated POR expression in both liver and small intestine, whereas treatment at 4 mg/kg led to a more targeted deletion in the liver. Using this approach, we have studied the pharmacokinetics of three probe drugs - paroxetine, midazolam, nelfinavir - and show that intestinal metabolism is a determinant of oral bioavailability for the two latter compounds. The Endogenous Reductase Locus (ERL) mouse represents a significant advance on previous POR deletion models as it allows direct comparison of hepatic and intestinal effects on drug and xenobiotic clearance using lower doses of a single Cre inducing agent, and in additionminimizes any cytotoxic effects, whichmay compromise interpretation of the experimental data.

    Original languageEnglish
    Pages (from-to)479-488
    Number of pages10
    JournalBiochemical Journal
    Volume465
    Issue number3
    Early online date7 Nov 2014
    DOIs
    Publication statusPublished - Feb 2015

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    Keywords

    • Conditional inducible deletion
    • Cytochrome P450 oxidoreductase
    • Drug bioavailability
    • Gut
    • Liver

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