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Research ArticleArticle

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug InteractionsGraphic

Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition February 2015, 43 (2) 235-247; DOI: https://doi.org/10.1124/dmd.114.059105
Saki Izumi
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Yoshitane Nozaki
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Kazuya Maeda
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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  • ORCID record for Kazuya Maeda
Takafumi Komori
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Osamu Takenaka
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Hiroyuki Kusuhara
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Yuichi Sugiyama
Drug Metabolism and Pharmacokinetics Japan, Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan (S.I., Y.N., T.K.); Pharmacokinetics and Pharmacodynamics, Morphotek Inc., Exton, Pennsylvania (O.T.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.S.)
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Abstract

The risk assessment of organic anion transporting polypeptide (OATP) 1B1–mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17β-glucuronide (E2G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The Ki values (μM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the Ki values were within 2.8-fold of those obtained using E2G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the Ki values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E2G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation.

Footnotes

    • Received May 13, 2014.
    • Accepted November 20, 2014.
  • This study was partly supported by Grants-in-Aid for Research on Publicly Essential Drugs and Medical Devices from the Ministry of Health, Labour and Welfare of Japan.

  • dx.doi.org/10.1124/dmd.114.059105.

  • Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (2)
Drug Metabolism and Disposition
Vol. 43, Issue 2
1 Feb 2015
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Research ArticleArticle

In Vitro Substrate-Dependent Inhibition of OATP1B1

Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition February 1, 2015, 43 (2) 235-247; DOI: https://doi.org/10.1124/dmd.114.059105

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Research ArticleArticle

In Vitro Substrate-Dependent Inhibition of OATP1B1

Saki Izumi, Yoshitane Nozaki, Kazuya Maeda, Takafumi Komori, Osamu Takenaka, Hiroyuki Kusuhara and Yuichi Sugiyama
Drug Metabolism and Disposition February 1, 2015, 43 (2) 235-247; DOI: https://doi.org/10.1124/dmd.114.059105
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