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)

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    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
    DOIs
    Publication statusPublished - 1 Feb 2015

    Fingerprint

    Metabolism
    Liver
    Biological Availability
    Pharmaceutical Preparations
    Nelfinavir
    NADPH-Ferrihemoprotein Reductase
    Oxygenases
    Paroxetine
    Methylcholanthrene
    Pharmacokinetics
    Midazolam
    Xenobiotics
    Cytochrome P-450 Enzyme System
    Small Intestine
    Oxidoreductases
    Genes
    Electrons
    Cre recombinase
    Therapeutics

    Keywords

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

    Cite this

    @article{e002ba41553241e597d2843bdf376c94,
    title = "Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability",
    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.",
    keywords = "Conditional inducible deletion, Cytochrome P450 oxidoreductase, Drug bioavailability, Gut, Liver",
    author = "Henderson, {Colin J.} and McLaughlin, {Lesley A.} and Maria Osuna-Cabello and Malcolm Taylor and Ian Gilbert and McLaren, {Aileen W.} and Wolf, {C. Roland}",
    year = "2015",
    month = "2",
    day = "1",
    doi = "10.1042/BJ20140582",
    language = "English",
    volume = "465",
    pages = "479--488",
    journal = "Biochemical Journal",
    issn = "0264-6021",
    publisher = "Portland Press",
    number = "3",

    }

    TY - JOUR

    T1 - Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

    AU - Henderson, Colin J.

    AU - McLaughlin, Lesley A.

    AU - Osuna-Cabello, Maria

    AU - Taylor, Malcolm

    AU - Gilbert, Ian

    AU - McLaren, Aileen W.

    AU - Wolf, C. Roland

    PY - 2015/2/1

    Y1 - 2015/2/1

    N2 - 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.

    AB - 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.

    KW - Conditional inducible deletion

    KW - Cytochrome P450 oxidoreductase

    KW - Drug bioavailability

    KW - Gut

    KW - Liver

    UR - http://www.scopus.com/inward/record.url?scp=84921767260&partnerID=8YFLogxK

    U2 - 10.1042/BJ20140582

    DO - 10.1042/BJ20140582

    M3 - Article

    C2 - 25377919

    AN - SCOPUS:84921767260

    VL - 465

    SP - 479

    EP - 488

    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    IS - 3

    ER -