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Research ArticleArticle

In Vitro Evaluation of Hepatic Transporter-Mediated Clinical Drug-Drug Interactions: Hepatocyte Model Optimization and Retrospective Investigation

Yi-an Bi, Emi Kimoto, Samantha Sevidal, Hannah M. Jones, Hugh A. Barton, Sarah Kempshall, Kevin M. Whalen, Hui Zhang, Chengjie Ji, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition June 2012, 40 (6) 1085-1092; DOI: https://doi.org/10.1124/dmd.111.043489
Yi-an Bi
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Emi Kimoto
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Samantha Sevidal
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Hannah M. Jones
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Hugh A. Barton
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Sarah Kempshall
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Kevin M. Whalen
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Hui Zhang
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Chengjie Ji
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Katherine S. Fenner
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Ayman F. El-Kattan
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Yurong Lai
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Abstract

To assess the feasibility of using sandwich-cultured human hepatocytes (SCHHs) as a model to characterize transport kinetics for in vivo pharmacokinetic prediction, the expression of organic anion-transporting polypeptide (OATP) proteins in SCHHs, along with biliary efflux transporters, was confirmed quantitatively by liquid chromatography-tandem mass spectrometry. Rifamycin SV (Rif SV), which was shown to completely block the function of OATP transporters, was selected as an inhibitor to assess the initial rates of active uptake. The optimized SCHH model was applied in a retrospective investigation of compounds with known clinically significant OATP-mediated uptake and was applied further to explore drug-drug interactions (DDIs). Greater than 50% inhibition of active uptake by Rif SV was found to be associated with clinically significant OATP-mediated DDIs. We propose that the in vitro active uptake value therefore could serve as a cutoff for class 3 and 4 compounds of the Biopharmaceutics Drug Disposition Classification System, which could be integrated into the International Transporter Consortium decision tree recommendations to trigger clinical evaluations for potential DDI risks. Furthermore, the kinetics of in vitro hepatobiliary transport obtained from SCHHs, along with protein expression scaling factors, offer an opportunity to predict complex in vivo processes using mathematical models, such as physiologically based pharmacokinetics models.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043489.

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

  • ABBREVIATIONS:

    OATP
    organic anion-transporting polypeptide
    AUC
    area under the curve
    DDI
    drug-drug interaction
    HBSS
    Hanks' balanced salt solution
    HPLC
    high-performance liquid chromatography
    ITC
    International Transporter Consortium
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    Rif SV
    rifamycin SV
    SCHH
    sandwich-cultured human hepatocyte
    SCRH
    sandwich-cultured rat hepatocyte
    SIL
    stable isotope label
    TC
    taurocholate.

  • Received October 28, 2011.
  • Accepted March 1, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (6)
Drug Metabolism and Disposition
Vol. 40, Issue 6
1 Jun 2012
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Research ArticleArticle

IN VITRO EVALUATION OF OATP-MEDIATED DDI

Yi-an Bi, Emi Kimoto, Samantha Sevidal, Hannah M. Jones, Hugh A. Barton, Sarah Kempshall, Kevin M. Whalen, Hui Zhang, Chengjie Ji, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1085-1092; DOI: https://doi.org/10.1124/dmd.111.043489

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Research ArticleArticle

IN VITRO EVALUATION OF OATP-MEDIATED DDI

Yi-an Bi, Emi Kimoto, Samantha Sevidal, Hannah M. Jones, Hugh A. Barton, Sarah Kempshall, Kevin M. Whalen, Hui Zhang, Chengjie Ji, Katherine S. Fenner, Ayman F. El-Kattan and Yurong Lai
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1085-1092; DOI: https://doi.org/10.1124/dmd.111.043489
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