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Research ArticleArticle

Investigation of Drug-Drug Interactions Caused by Human Pregnane X Receptor-Mediated Induction of CYP3A4 and CYP2C Subfamilies in Chimeric Mice with a Humanized Liver

Maki Hasegawa, Harunobu Tahara, Ryo Inoue, Masakazu Kakuni, Chise Tateno and Junko Ushiki
Drug Metabolism and Disposition March 2012, 40 (3) 474-480; DOI: https://doi.org/10.1124/dmd.111.042754
Maki Hasegawa
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Harunobu Tahara
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Ryo Inoue
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Masakazu Kakuni
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Chise Tateno
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Junko Ushiki
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Abstract

The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(−)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(−)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.042754.

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

  • ABBREVIATIONS:

    P450
    cytochrome P450
    DDI
    drug-drug interaction
    PXR
    pregnane X receptor
    MDR
    multidrug resistance gene
    MRP
    multidrug resistance-associated protein
    UGT
    UDP-glucuronosyltransferase
    RIF
    rifampicin
    ROS
    rosiglitazone
    WAR
    (S)-warfarin
    MEP
    (S)-(−)-mephenytoin
    TRZ
    triazolam
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    PCR
    polymerase chain reaction
    G-6-P
    d-glucose 6-phosphate
    G-6-P-DH
    G-6-P dehydrogenase
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    AUC
    area under the plasma concentration-time curve.

  • Received September 14, 2011.
  • Accepted November 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

INDUCTION OF CYP3A4 AND CYP2C SUBFAMILIES IN PXB MICE

Maki Hasegawa, Harunobu Tahara, Ryo Inoue, Masakazu Kakuni, Chise Tateno and Junko Ushiki
Drug Metabolism and Disposition March 1, 2012, 40 (3) 474-480; DOI: https://doi.org/10.1124/dmd.111.042754

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Research ArticleArticle

INDUCTION OF CYP3A4 AND CYP2C SUBFAMILIES IN PXB MICE

Maki Hasegawa, Harunobu Tahara, Ryo Inoue, Masakazu Kakuni, Chise Tateno and Junko Ushiki
Drug Metabolism and Disposition March 1, 2012, 40 (3) 474-480; DOI: https://doi.org/10.1124/dmd.111.042754
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