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Molecular Pharmacology

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Research ArticleArticle

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Maki Hasegawa, Yury Kapelyukh, Harunobu Tahara, Jost Seibler, Anja Rode, Sylvia Krueger, Dongtao N. Lee, C. Roland Wolf and Nico Scheer
Molecular Pharmacology September 2011, 80 (3) 518-528; DOI: https://doi.org/10.1124/mol.111.071845
Maki Hasegawa
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Yury Kapelyukh
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Harunobu Tahara
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Jost Seibler
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Anja Rode
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Sylvia Krueger
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Dongtao N. Lee
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C. Roland Wolf
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Nico Scheer
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Abstract

Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported in part by ITI Life Sciences, Scotland.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071845.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    PXR
    pregnane X receptor
    CAR
    constitutive androstane receptor
    RIF
    rifampicin
    PCN
    pregnenolone-16α-carbonitrile
    hu
    humanized
    BAC
    bacterial artificial chromosome
    ES
    embryonic stem
    WT
    wild type
    PCR
    polymerase chain reaction
    SUL
    sulfinpyrazone
    PIO
    pioglitazone
    TRZ
    triazolam
    AUC
    area under the plasma concentration-time curve
    qRT
    quantitative reverse transcriptase
    MDZ
    midazolam
    DBF
    dibenzylfluorescein
    apoE
    apolipoprotein E.

  • Received February 21, 2011.
  • Accepted May 31, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Maki Hasegawa, Yury Kapelyukh, Harunobu Tahara, Jost Seibler, Anja Rode, Sylvia Krueger, Dongtao N. Lee, C. Roland Wolf and Nico Scheer
Molecular Pharmacology September 1, 2011, 80 (3) 518-528; DOI: https://doi.org/10.1124/mol.111.071845

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Research ArticleArticle

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Maki Hasegawa, Yury Kapelyukh, Harunobu Tahara, Jost Seibler, Anja Rode, Sylvia Krueger, Dongtao N. Lee, C. Roland Wolf and Nico Scheer
Molecular Pharmacology September 1, 2011, 80 (3) 518-528; DOI: https://doi.org/10.1124/mol.111.071845
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