Defining human pathways of drug metabolism in vivo through the development of a multiple humanized mouse model

Nico Scheer, Yury Kapelyukh, Anja Rode, Stefan Oswald, Diana Busch, Lesley A. McLaughlin, De Lin, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    Variability in drug pharmacokinetics is a major factor in defining drug efficacy and side effects. There remains an urgent need, particularly with the growing use of polypharmacy, to obtain more informative experimental data predicting clinical outcomes. Major species differences in multiplicity, substrate specificity, and regulation of enzymes from the cytochrome P450-dependent mono-oxygenase system play a critical role in drug metabolism. To develop an in vivo model for predicting human responses to drugs, we generated a mouse, where 31 P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene families were exchanged for their relevant human counterparts. The model has been improved through additional humanization for the nuclear receptors constitutive androgen receptor and pregnane X receptor that control the expression of key drug metabolizing enzymes and transporters. In this most complex humanized mouse model reported to date, the cytochromes P450 function as predicted and we illustrate how these mice can be applied to predict drug-drug interactions in humans
    Original languageEnglish
    Pages (from-to)1679-1690
    Number of pages12
    JournalDrug Metabolism and Disposition
    Volume43
    Issue number11
    Early online date11 Aug 2015
    DOIs
    Publication statusPublished - Nov 2015

    Fingerprint

    Pharmaceutical Preparations
    Cytochrome P-450 Enzyme System
    Polypharmacy
    Oxygenases
    Androgen Receptors
    Enzymes
    Cytoplasmic and Nuclear Receptors
    Substrate Specificity
    Drug-Related Side Effects and Adverse Reactions
    Drug Interactions
    Genes
    Pharmacokinetics
    pregnane X receptor

    Cite this

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    title = "Defining human pathways of drug metabolism in vivo through the development of a multiple humanized mouse model",
    abstract = "Variability in drug pharmacokinetics is a major factor in defining drug efficacy and side effects. There remains an urgent need, particularly with the growing use of polypharmacy, to obtain more informative experimental data predicting clinical outcomes. Major species differences in multiplicity, substrate specificity, and regulation of enzymes from the cytochrome P450-dependent mono-oxygenase system play a critical role in drug metabolism. To develop an in vivo model for predicting human responses to drugs, we generated a mouse, where 31 P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene families were exchanged for their relevant human counterparts. The model has been improved through additional humanization for the nuclear receptors constitutive androgen receptor and pregnane X receptor that control the expression of key drug metabolizing enzymes and transporters. In this most complex humanized mouse model reported to date, the cytochromes P450 function as predicted and we illustrate how these mice can be applied to predict drug-drug interactions in humans",
    author = "Nico Scheer and Yury Kapelyukh and Anja Rode and Stefan Oswald and Diana Busch and McLaughlin, {Lesley A.} and De Lin and Henderson, {Colin J.} and Wolf, {C. Roland}",
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    Defining human pathways of drug metabolism in vivo through the development of a multiple humanized mouse model. / Scheer, Nico; Kapelyukh, Yury; Rode, Anja; Oswald, Stefan; Busch, Diana; McLaughlin, Lesley A.; Lin, De; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author).

    In: Drug Metabolism and Disposition, Vol. 43, No. 11, 11.2015, p. 1679-1690.

    Research output: Contribution to journalArticle

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    AU - Henderson, Colin J.

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    AB - Variability in drug pharmacokinetics is a major factor in defining drug efficacy and side effects. There remains an urgent need, particularly with the growing use of polypharmacy, to obtain more informative experimental data predicting clinical outcomes. Major species differences in multiplicity, substrate specificity, and regulation of enzymes from the cytochrome P450-dependent mono-oxygenase system play a critical role in drug metabolism. To develop an in vivo model for predicting human responses to drugs, we generated a mouse, where 31 P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene families were exchanged for their relevant human counterparts. The model has been improved through additional humanization for the nuclear receptors constitutive androgen receptor and pregnane X receptor that control the expression of key drug metabolizing enzymes and transporters. In this most complex humanized mouse model reported to date, the cytochromes P450 function as predicted and we illustrate how these mice can be applied to predict drug-drug interactions in humans

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