Development of herb glycoside-mimic prodrugs for colon-specific delivery -A trial research-

用于结肠特异性递送的草本糖苷模拟前药的开发-试验研究-

• 批准号: 09672219
• 负责人: AKAO Teruaki
• 金额: $ 1.15万
• 依托单位: Toyama Medical and Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672219/
• 关键词: Glycoside; Colon Delivery; Salicylic Acid; Intestinal Bacteria; Prodrug; 非ステロイド性抗炎症剤; 抗癌剤

Herbs contain many kinds of glycosides as main and effective constituents. Through our studies regarding metabolic fates and actions of popular natural glycosides in relation to intestinal bacteria, we have clarified that these glycosides are prodrugs delivered to colon and activated by intestinal bacteria.The aim of our project is to develop glycoside-mimic prodrugs of anti-inflammatory and anti-cancer prodrugs, which are delivered to colon and activated by intestinal bacteria there, for therapeutics of ulcerative colitis and colonic cancer, respectively.Recently, salicylate, an anti-inflammatory drug, attracts notice by means of inhibiting COX-2, suppressing inducible COX-2 gene transcription, inhibiting NF-ィイD2κィエD2B, anti-oxidative action, etc.In this project, I synthesized salicylic acid glycosides. They were much poorly absorbed in rat everted intestine in comparison with salicylic acid, delivered to rat cecum after oral administration, and hydrolyzed to salicylic acid by intestinal bacteria there. The glycosides showed mild antipyretic effects against yeat-induced fever without causing stomach ulcer in rats. Moreover, salicylic acid-o-glucoside improved dextran sulfate-induced colitis in rats in relation to suppressing wheight loss, the decrease of hematocrit value, ocult bleeding, and the formation of colonic erosion. Thus, it is clear that salicylic acid glycosides are prodrugs for colon-specific delivery without adverse effects and suggested to be a good drug for ulcerative colitis.Also, ginsenoside Rb1, a major glycoside of Panax ginseng, was shown to be a prodrug delivered to rat cecum and activated to compound K by intestinal bacteria.

中草药中含有多种糖苷类化合物，是其主要有效成分。通过对常见天然糖苷与肠道细菌的代谢命运和作用的研究，我们明确了这些糖苷是被肠道细菌激活并转运到结肠的前体药物。本项目的目的是开发抗炎和抗癌前体药物的类似糖苷类药物，并将其输送到结肠并由肠道细菌激活，分别用于治疗溃疡性结肠炎和结肠癌。近年来，水杨酸盐作为一种抗炎药物，通过抑制COX-2、抑制诱导性COX-2基因转录、抑制NF-ィイD2κィエD2B、抗氧化作用等途径而引起人们的关注。我合成了水杨酸糖苷。与水杨酸相比，它们在大鼠外翻肠道中的吸收较差，经口给药后被大鼠盲肠给药，并被那里的肠道细菌水解为水杨酸。总苷对大鼠发热有轻微的解热作用，且不引起大鼠胃溃疡。此外，水杨酸-o-葡萄糖苷可改善葡聚糖硫酸酯诱导的大鼠结肠炎，其作用与抑制体重丧失、红细胞压积降低、少量出血和结肠糜烂形成有关。由此可见，水杨酸糖苷是一种结肠靶向给药，无不良反应，是治疗溃疡性结肠炎的良好药物。人参皂苷Rb1是人参的主要糖苷，是一种经盲肠传递的前药，可被肠道细菌激活为化合物K。

项目成果

Teruaki Akao et al.: "Appearance of compound K,a major metabolite of ginsenoside Rb1 by intestinal bacteria,in a rat plasma after oral administration" Biol.Pharm.Bull.21巻・3号. 245-249 (1998)

Teruaki Akao 等人：“口服给药后大鼠血浆中化合物 K（肠道细菌对人参皂苷 Rb1 的主要代谢物）的外观”Biol.Pharm.Bull.Volume 21，Issue 3. 245-249 (1998)

Teruaki Akao: "Appearance of compound K,a major metabolite of ginsenoside Rb_1 by intestinal bacteria,in a rat plasma after oral administration" Biol.Pharm.Bull.21巻3号. 245-249 (1998)

Teruaki Akao：“口服给药后大鼠血浆中化合物 K（肠道细菌对人参皂苷 Rb_1 的主要代谢物）的外观”Biol.Pharm.Bull.Vol. 21，No. 3. 245-249 (1998)