Activation status of the Pregnane X Receptor influences Vemurafenib availability in humanized mouse models

A. Kenneth MacLeod, Lesley A. McLaughlin, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    Vemurafenib is a revolutionary treatment for melanoma, but the magnitude of therapeutic response is highly variable, and the rapid acquisition of resistance is frequent. Here, we examine how vemurafenib disposition, particularly through cytochrome P450-mediated oxidation pathways, could potentially influence these outcomes using a panel of knockout and transgenic humanized mouse models. We identified CYP3A4 as the major enzyme involved in the metabolism of vemurafenib in in vitro assays with human liver microsomes. However, mice expressing human CYP3A4 did not process vemurafenib to a greater extent than CYP3A4-null animals, suggesting that other pregnane X receptor (PXR)-regulated pathways may contribute more significantly to vemurafenib metabolism in vivo. Activation of PXR, but not of the closely related constitutive androstane receptor, profoundly reduced circulating levels of vemurafenib in humanized mice. This effect was independent of CYP3A4 and was negated by cotreatment with the drug efflux transporter inhibitor elacridar. Finally, vemurafenib strongly induced PXR activity in vitro, but only weakly induced PXR in vivo. Taken together, our findings demonstrate that vemurafenib is unlikely to exhibit a clinically significant interaction with CYP3A4, but that modulation of bioavailability through PXR-mediated regulation of drug transporters (e.g., by other drugs) has the potential to markedly influence systemic exposure and thereby therapeutic outcomes
    Original languageEnglish
    Pages (from-to)4573-4581
    Number of pages10
    JournalCancer Research
    Volume75
    Issue number21
    Early online date11 Sep 2015
    DOIs
    Publication statusPublished - 1 Nov 2015

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    Cytochrome P-450 CYP3A
    PLX4032
    pregnane X receptor
    Drug and Narcotic Control
    Liver Microsomes
    Pharmaceutical Preparations
    Cytochrome P-450 Enzyme System
    Transgenic Mice
    Biological Availability
    Melanoma
    Enzymes
    Therapeutics

    Cite this

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    abstract = "Vemurafenib is a revolutionary treatment for melanoma, but the magnitude of therapeutic response is highly variable, and the rapid acquisition of resistance is frequent. Here, we examine how vemurafenib disposition, particularly through cytochrome P450-mediated oxidation pathways, could potentially influence these outcomes using a panel of knockout and transgenic humanized mouse models. We identified CYP3A4 as the major enzyme involved in the metabolism of vemurafenib in in vitro assays with human liver microsomes. However, mice expressing human CYP3A4 did not process vemurafenib to a greater extent than CYP3A4-null animals, suggesting that other pregnane X receptor (PXR)-regulated pathways may contribute more significantly to vemurafenib metabolism in vivo. Activation of PXR, but not of the closely related constitutive androstane receptor, profoundly reduced circulating levels of vemurafenib in humanized mice. This effect was independent of CYP3A4 and was negated by cotreatment with the drug efflux transporter inhibitor elacridar. Finally, vemurafenib strongly induced PXR activity in vitro, but only weakly induced PXR in vivo. Taken together, our findings demonstrate that vemurafenib is unlikely to exhibit a clinically significant interaction with CYP3A4, but that modulation of bioavailability through PXR-mediated regulation of drug transporters (e.g., by other drugs) has the potential to markedly influence systemic exposure and thereby therapeutic outcomes",
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    Activation status of the Pregnane X Receptor influences Vemurafenib availability in humanized mouse models. / MacLeod, A. Kenneth; McLaughlin, Lesley A.; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author).

    In: Cancer Research, Vol. 75, No. 21, 01.11.2015, p. 4573-4581.

    Research output: Contribution to journalArticle

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