The Potential for an Interaction between MRP2 (ABCC2) and Various Therapeutic Agents : Probenecid as a Candidate Inhibitor of the Biliary Excretion of Irinotecan Metabolites

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著者

    • KATO Yukio
    • Graduate School of Pharmaceutical Sciences, University of Tokyo; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation
    • SUGIYAMA Yuichi
    • Graduate School of Pharmaceutical Sciences, University of Tokyo; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation

抄録

  Irinotecan hydrochloride (CPT-11) is an anticancer agent with unpredictable bouts of diarrhea as a dose-limiting toxic side-effect. Since the biliary excretion of its active metabolite (SN-38) and SN-38 glucuronide (SN38-Glu), which are mediated by the multidrug resistance associated protein-2 (MRP2/ABCC2), has been proposed to be related to this gastrointestinal toxicity, we have attempted here to examine the potential of various therapeutic agents to interact with the biliary excretion in order to identify MRP2 inhibitors to prevent this toxicity. The inhibition constants (<i>K</i><sub>i</sub>) of 26 compounds were examined for the transport of a typical MRP2 substrate in isolated canalicular membrane vesicles. Of these, 13 compounds inhibited the transport with <i>K</i><sub>i</sub> values from 0.0461 to 281 μM. Three inhibitors (probenecid, sulfobromophthalein and glycyrrhizin) were also found to inhibit the biliary excretion of SN-38 and SN38-Glu in rats <i>in vivo</i>, and the degrees of inhibition were compatible with the estimated values based on the ratios of <i>K</i><sub>i</sub> and unbound concentrations in circulating plasma. A similar estimation of the potential inhibitory effect in human was also examined by considering both the <i>K</i><sub>i</sub> of each therapeutic agent and its unbound concentration both in circulating plasma and the inlet to the liver. The predicted degrees of inhibition by most compounds were minimal whereas approximately 75% inhibition was predicted for probenecid. Thus, probenecid may be a candidate which can be used clinically to inhibit the biliary excretion of CPT-11 metabolites, whereas an interaction between most of the other compounds and MRP2 is more unlikely.<br>

収録刊行物

  • Drug metabolism and pharmacokinetics

    Drug metabolism and pharmacokinetics 17(1), 23-33, 2002-03-29

    The Japanese Society for the Study of Xenobiotics

参考文献:  49件中 1-49件 を表示

被引用文献:  4件中 1-4件 を表示

各種コード

  • NII論文ID(NAID)
    10008197948
  • NII書誌ID(NCID)
    AA1162652X
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    09161139
  • データ提供元
    CJP書誌  CJP引用  J-STAGE 
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