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Research ArticleArticle

Investigation of Endogenous Compounds Applicable to Drug–Drug Interaction Studies Involving the Renal Organic Anion Transporters, OAT1 and OAT3, in Humans

Yuri Tsuruya, Koji Kato, Yamato Sano, Yuichiro Imamura, Kazuya Maeda, Yuji Kumagai, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition December 2016, 44 (12) 1925-1933; DOI: https://doi.org/10.1124/dmd.116.071472
Yuri Tsuruya
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Koji Kato
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Yamato Sano
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Yuichiro Imamura
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Kazuya Maeda
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Yuji Kumagai
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Yuichi Sugiyama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (Y.T., Y.Sa., K.M., H.K.); Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan (K.K.); Drug Metabolism and Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Tokyo, Japan (Y.I.); Clinical Trial Center, Kitasato University Hospital, Kanagawa, Japan (Y.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (Y.Su.)
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Abstract

This study was a comprehensive analysis of metabolites in plasma and urine specimens from subjects who received probenecid, a potent inhibitor of renal organic anion transporters (OATs). Taurine and glycochenodeoxycholate sulfate (GCDCA-S) could be identified using authentic standards. Probenecid had no effect on the area under the plasma–concentration time curves of taurine and GCDCA-S, whereas it significantly inhibited their urinary excretion in a dose-dependent manner. Probenecid at 500, 750, and 1500 mg orally decreased the renal clearance (CLR) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CLR values correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6β-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with Km values of 379 ± 58 and 64.3 ± 3.9 μM, respectively. The Ki values of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 ± 1.27 and 7.40 ± 0.70 μM, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CLR of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and Ki values. These results suggest that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug–drug interactions involving OAT1 and OAT3, respectively, in humans.

Footnotes

    • Received May 7, 2016.
    • Accepted September 14, 2016.
  • This research was partially supported by the Research on Development of New Drugs project of the Japan Agency for Medical Research and Development.

  • dx.doi.org/10.1124/dmd.116.071472.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Research ArticleArticle

Endogenous Probes of OAT1 and OAT3

Yuri Tsuruya, Koji Kato, Yamato Sano, Yuichiro Imamura, Kazuya Maeda, Yuji Kumagai, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1925-1933; DOI: https://doi.org/10.1124/dmd.116.071472

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Research ArticleArticle

Endogenous Probes of OAT1 and OAT3

Yuri Tsuruya, Koji Kato, Yamato Sano, Yuichiro Imamura, Kazuya Maeda, Yuji Kumagai, Yuichi Sugiyama and Hiroyuki Kusuhara
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1925-1933; DOI: https://doi.org/10.1124/dmd.116.071472
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