Thienopyridine P2Y12 receptor antagonists:unknown pharmacological active metabolites and metabolic activation mechanisms

  • Hagihara Katsunobu
    Drug Metabolism & Pharmacokinetics Res. Labs., Daiichi Sankyo Co., Ltd.
  • Kazui Miho
    Drug Metabolism & Pharmacokinetics Res. Labs., Daiichi Sankyo Co., Ltd.
  • Kurihara Atsushi
    Drug Metabolism & Pharmacokinetics Res. Labs., Daiichi Sankyo Co., Ltd.
  • Ando Osamu
    Drug Metabolism & Pharmacokinetics Res. Labs., Daiichi Sankyo Co., Ltd.
  • Izumi Takashi
    Research Function, Daiichi Sankyo Co., Ltd.
  • Ikeda Toshihiko
    Laboratory of Pharmacokinetics, Yokohama University of Pharmacy

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Other Title
  • チエノピリジン系P2Y12受容体阻害剤:長らく不明だった薬理活性体と活性化メカニズム
  • チエノピリジンケイ P2Y12 ジュヨウタイ ソガイザイ : ナガラク フメイ ダッタ ヤクリ カッセイタイ ト カッセイカ メカニズム

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Abstract

As sulfa drug was found as the urinary metabolite of Prontosil in past times, early prodrugs were often discovered by chance. The prodrugs later on, however, have been synthesized by chemically modifying the pharmacologically active substance, most frequently, with an intension of increased lipophilicity for an improved intestinal absorption and efficient enzymatic conversion to the active substance in the body. This could be achieved based on plenty of knowledge on the activating enzymes like esterases. In cases where the chemical structures of active metabolites or the mechanisms of metabolic activation are unknown, however, we cannot implement such strategies. The examples are the thienopyridine antiplatelet agents whose active metabolites have not been structurally clarified for long even though their clinical usefulness as the anti-platelet drugs has been well established in human studies. In this article, we describe the mechanisms for metabolic activation of thienopyridines and impact of the differenes in the activation mechanism on the clinical outcomes.

Journal

  • Drug Delivery System

    Drug Delivery System 30 (5), 454-464, 2015

    THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM

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