Characterization of CS-023 (RO4908463), a Novel Parenteral Carbapenem Antibiotic, and Meropenem as Substrates of Human Renal Transporters

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著者

    • SUGIYAMA Daisuke
    • Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
    • KAMIYAMA Emi
    • Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
    • TOKUI Taro
    • Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
    • HIROTA Takashi
    • Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
    • IKEDA Toshihiko
    • Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.

抄録

  To characterize the renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem in humans, we examined their affinities as substrates to human renal transporters. <i>In vitro</i> studies on the uptake of [<sup>14</sup>C]CS-023 and [<sup>14</sup>C]meropenem were conducted using HEK293 cells expressing human organic anion transporters (hOAT) 1, hOAT3, hOAT4, and the human organic cation transporters (hOCT) 1 and hOCT2. CS-023 did not serve as the substrate for any of the transporters tested. On the other hand, meropenem was transported by hOAT1 and hOAT3. The <i>K</i><sub>m</sub> value of the hOAT3-mediated transport was 847 μM, and the uptake was inhibited by probenecid, <i>p</i>-aminohippurate and benzylpenicillin with <i>K</i><sub>i</sub> values of 3.76, 712, and 202 μM, respectively. One of the reasons why CS-023 is not a substrate of hOATs, and vice versa for meropenem, would be that a very small proportion of CS-023 exists as the anionic form at the physiological pH, whereas 50% of meropenem exists as the anionic form. These findings indicate that the lack of recognition of CS-023 by renal transporters is one of the reasons for its long plasma half-life in humans compared with meropenem which undergoes renal tubular secretion mediated by hOAT1 and hOAT3.<br>

収録刊行物

  • Drug metabolism and pharmacokinetics  

    Drug metabolism and pharmacokinetics 22(1), 41-47, 2007-02-28 

    The Japanese Society for the Study of Xenobiotics

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各種コード

  • NII論文ID(NAID)
    10018732973
  • NII書誌ID(NCID)
    AA1162652X
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    13474367
  • データ提供元
    CJP書誌  CJP引用  J-STAGE 
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