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Research ArticleSpecial Section on Transporters in Toxicity and Disease

6β-Hydroxycortisol Is an Endogenous Probe for Evaluation of Drug–Drug Interactions Involving a Multispecific Renal Organic Anion Transporter, OAT3/SLC22A8, in Healthy Subjects

Yuichiro Imamura, Yuri Tsuruya, Katja Damme, Dominik Heer, Yuji Kumagai, Kazuya Maeda, Nobuyuki Murayama, Noriko Okudaira, Atsushi Kurihara, Takashi Izumi, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition April 2014, 42 (4) 685-694; DOI: https://doi.org/10.1124/dmd.113.055475
Yuichiro Imamura
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Yuri Tsuruya
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Katja Damme
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Dominik Heer
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Yuji Kumagai
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Kazuya Maeda
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Nobuyuki Murayama
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Noriko Okudaira
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Atsushi Kurihara
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Takashi Izumi
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Yuichi Sugiyama
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Hiroyuki Kusuhara
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.)
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Abstract

6β-Hydroxycortisol (6β-OHF) is a substrate of the organic anion transporter 3 (OAT3) and the multidrug and toxin extrusion proteins MATE1 and MATE-2K in the corresponding cDNA-transfected cells. This study aimed to examine the contribution of OAT3 and MATEs to the urinary excretion of 6β-OHF in humans using the appropriate in vivo inhibitors, probenecid and pyrimethamine, for OAT3 and MATEs, respectively. Oat3(–/–) mice showed significantly reduced renal clearance of 6β-OHF (CLrenal, 6β-OHF) compared with wild-type mice (18.1 ± 1.5 versus 7.60 ± 1.8 ml/min/kg). 6β-OHF uptake by human kidney slices was inhibited significantly by probenecid to 20–45% of the control values and partly by 1-methyl-4-phenylpyridinium. 6β-OHF plasma concentration and the amount of 6β-OHF excreted into the urine (X6β-OHF) were measured in healthy subjects enrolled in drug-drug interaction studies of benzylpenicillin alone or with probenecid (study 1), adefovir alone or with probenecid (study 2), and metformin alone or with pyrimethamine (study 3). Probenecid treatment caused a 57 and 76% increase in the area under the plasma concentration–time curve for 6β-OHF (AUC6β-OHF) in studies 1 and 2, respectively, but did not affect X6β-OHF. Consequently, CLrenal, 6β-OHF (milliliters per minute) decreased significantly from 231 ± 11 to 135 ± 9 and from 225 ± 26 to 141 ± 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC6β-OHF nor CLrenal, 6β-OHF was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6β-OHF, and that 6β-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.

Footnotes

    • Received October 17, 2013.
    • Accepted January 30, 2014.
  • The study was sponsored by Daiichi-Sankyo Co., Ltd, Tokyo, Japan. This study was also supported by Grants-in-Aid for Public-Private Sector Joint Research on Publicly Essential Drugs (KHB 1208) from the Japan Health Sciences Foundation, Grant-in-Aid for Scientific Research (S) [Grant 24229002], for Scientific Research (B) [Grant 23390034], and for Challenging Exploratory Research [Grant 24659071] from the Japan Society for the Promotion of Science, Japan.

  • Y.I., N.M., N.O., A.K., and T.I. are employees of Daiichi Sankyo Co., Ltd. K.D. and D.H. are employees of Daiichi Sankyo Europe GmbH. The remaining authors declare no conflict of interest.

  • dx.doi.org/10.1124/dmd.113.055475.

  • ↵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: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleSpecial Section on Transporters in Toxicity and Disease

6β-Hydroxycortisol as Endogenous In Vivo Probe for OAT3

Yuichiro Imamura, Yuri Tsuruya, Katja Damme, Dominik Heer, Yuji Kumagai, Kazuya Maeda, Nobuyuki Murayama, Noriko Okudaira, Atsushi Kurihara, Takashi Izumi, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition April 1, 2014, 42 (4) 685-694; DOI: https://doi.org/10.1124/dmd.113.055475

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Research ArticleSpecial Section on Transporters in Toxicity and Disease

6β-Hydroxycortisol as Endogenous In Vivo Probe for OAT3

Yuichiro Imamura, Yuri Tsuruya, Katja Damme, Dominik Heer, Yuji Kumagai, Kazuya Maeda, Nobuyuki Murayama, Noriko Okudaira, Atsushi Kurihara, Takashi Izumi, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition April 1, 2014, 42 (4) 685-694; DOI: https://doi.org/10.1124/dmd.113.055475
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