Prodrug for Bioreductive Activation-Independent Delivery of Menahydroquinone-4 : Human Liver Enzymatic Activation and Its Action in Warfarin-Poisoned Human Liver

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概要

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• The N, N-dimethylglycine esters of menahydroquinone-4 (1-mono, 1; 4-mono, 2; 1,4-bis, 3) were established in previous reports as prodrugs that could achieve the systemic bioreductive activation-independent delivery of menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4), in rat. The present study was undertaken to investigate if the prodrugs could undergo cleavage to parent drug (MKH) by a human tissues enzyme catalyzed hydrolytic pathway, the mechanism of the prodrugs for vitamin K-dependent carboxylation in human liver and their action in the warfarin poisoned human liver. The hydrolysis of the esters was shown to be catalyzed by esterases located in human liver but not in human plasma. The susceptibility of the esters to undergo human liver esterase hydrolysis was afected by the esterified position : 1>2>3. By using a human liver microsomal test system, the stimulation of vitamin K-dependent carboxylation with the prodrugs was determined. The prodrug could stimulate the carboxylation activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of MK-4. The carboxylation activity of the prodrug was strongly inhibited in the presence of eserine, an esterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoned conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrug could generate MKH in human liver (active site), and that the resultant MKH could act as a cofactor for the carboxylase without reductive activation processes of MK-4 to MKH. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristic of the prodrug leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients with coumarin and cephalosporin therapies.

• 公益社団法人日本薬学会の論文
• 1999-02-15

著者

• Iwasaki Hiroshi

  Department of Pathology, Faculty of Medicine, Fukuoka University

• Matsunaga Keiji

  Graduate School Of Pharmaceutical Sciences Kyoto University

• Iwasaki Hiroshi

  Department Of Anesthesiology And Critical Care Medicine Asahikawa Medical College

• Takata Jiro

  Laboratory Of Drug Design And Drug Delivery Faculty Of Pharmaceutical Sciences Fukuoka University

• MATSUNAGA Kazuhisa

  Faculty of Pharmaceutical Sciences, Fukuoka University

• TAKATA Jiro

  Faculty of Pharmaceutical Sciences, Fukuoka University

• KARUBE Yoshiharu

  Faculty of Pharmaceutical Sciences, Fukuoka University

• Karube Yoshiharu

  Faculty Of Pharmaceutical Sciences Fukuoka University

• Matsunaga Kazuhisa

  Faculty Of Pharmaceutical Sciences Fukuoka University

• YOSHIDA Keisuke

  Faculty of Pharmaceutical Sciences, Fukuoka University

• Matsunaga K

  Faculty Of Pharmaceutical Sciences Fukuoka University

• Takata Jiro

  Faculty Of Pharmaceutical Sciences Fukuoka University

• Hanada Motoki

  Faculty Of Pharmaceutical Sciences Kobe Gakuin University

• HANADA Mitsunobu

  Faculty of Pharmaceutical Sciences, Fukuoka University

• Mihashi Kunihide

  Faculty Of Pharmaceutical Sciences Fukuoka University

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