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Research ArticleArticle

Rifampin-Mediated Induction of Tamoxifen Metabolism in a Humanized PXR-CAR-CYP3A4/3A7-CYP2D6 Mouse Model

Jae H. Chang, John Chen, Liling Liu, Kirsten Messick and Justin Ly
Drug Metabolism and Disposition November 2016, 44 (11) 1736-1741; DOI: https://doi.org/10.1124/dmd.116.072132
Jae H. Chang
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California
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John Chen
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California
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Liling Liu
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California
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Kirsten Messick
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California
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Justin Ly
Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, California
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Abstract

Animals are not commonly used to assess drug-drug interactions due to poor clinical translatability arising from species differences that may exist in drug-metabolizing enzymes and transporters, and their regulation pathways. In this study, a transgenic mouse model expressing human pregnane X receptor (PXR), constitutive androstane receptor (CAR), CYP3A4/CYP3A7, and CYP2D6 (Tg-composite) was used to investigate the effect of induction mediated by rifampin on the pharmacokinetics of tamoxifen and its metabolites. In humans, tamoxifen is metabolized primarily by CYP3A4 and CYP2D6, and multiple-day treatment with rifampin decreased tamoxifen exposure by 6.2-fold. Interestingly, exposure of tamoxifen metabolites 4-hydroxytamoxifen (4OHT), N-desmethyltamoxifen (NDM), and endoxifen also decreased. In the Tg-composite model, pretreatment with rifampin decreased tamoxifen area under the time-concentration curve between 0 and 8 hours (AUC0-8) from 0.82 to 0.20 µM*h, whereas AUC0-8 of 4OHT, NDM, and endoxifen decreased by 3.4-, 4.7-, and 1.3-fold, respectively, mirroring the clinic observations. In the humanized PXR-CAR (hPXR-CAR) model, rifampin decreased AUC0-8 of tamoxifen and its metabolites by approximately 2-fold. In contrast, no significant modulation by rifampin was observed in the nonhumanized C57BL/6 (wild-type) animals. In vitro kinetics determined in microsomes prepared from livers of the Tg-composite animals showed that, although Km values were not different between vehicle- and rifampin-treated groups, rifampin increased the Vmax for the CYP3A4-mediated pathways. These data demonstrate that, although the hPXR-CAR model is responsive to rifampin, the extent of the clinical rifampin-tamoxifen interaction is better represented by the Tg-composite model. Consequently, the Tg-composite model may be a suitable tool to examine the extent of rifampin-mediated induction for other compounds whose metabolism is mediated by CYP3A4 and/or CYP2D6.

Footnotes

    • Received June 17, 2016.
    • Accepted August 17, 2016.
  • dx.doi.org/10.1124/dmd.116.072132.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (11)
Drug Metabolism and Disposition
Vol. 44, Issue 11
1 Nov 2016
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Research ArticleArticle

Rifampin-Mediated Induction of Tamoxifen in Humanized Mice

Jae H. Chang, John Chen, Liling Liu, Kirsten Messick and Justin Ly
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1736-1741; DOI: https://doi.org/10.1124/dmd.116.072132

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Research ArticleArticle

Rifampin-Mediated Induction of Tamoxifen in Humanized Mice

Jae H. Chang, John Chen, Liling Liu, Kirsten Messick and Justin Ly
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1736-1741; DOI: https://doi.org/10.1124/dmd.116.072132
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