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Characterization of renal excretion mechanism for a novel diuretic, M17055, in rats

Authors

  • Tomohiro Nishimura,

    1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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  • Yukio Kato,

    1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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  • Yoshimichi Sai,

    1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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  • Takuo Ogihara,

    1. Drug Metabolism and Pharmacokinetics Laboratory Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-uenohara, Gotemba, Shizuoka, 412-8542, Japan
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  • Akira Tsuji

    Corresponding author
    1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
    • Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Telephone: +81-76-234-4479; Fax: +81-76-264-6284
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Abstract

M17055 was developed as a novel diuretic that inhibits both Na+, K+, and 2Cl cotransport at the thick ascending Henle's loop and Na+ reuptake at the distal tubule. It is secreted at the renal proximal tubules. The purpose of the present study was to characterize the renal excretion mechanism of M17055. We used the renal cortical slices and brush border membrane vesicles (BBMVs) to investigate the transport mechanisms across the basolateral and brush border membranes, respectively. M17055 uptake by rat renal slices increased with time and was saturable. Several organic anions including probenecid, para-aminohippurate (PAH), and estrone-3-sulfate, decreased M17055 uptake. The uptake of M17055 was also observed into HEK293 cells expressing rat OAT1, and was inhibited by PAH. M17055 uptake by BBMVs was time-dependent, saturable, osmolarity-sensitive, and inhibited by several organic anions, but not by PAH. These results suggest that plural organic anion transport systems are involved in M17055 transport via both basolateral and brush border membranes of proximal tubule epithelial cells, a part of the renal uptake being mediated by OAT1. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2558–2566, 2004

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