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Pharmacokinetic and Cellular Biological Study on Colonic Absorption : Strategies for Optimized Controlled Release Oral Drug Delivery

结肠吸收的药代动力学和细胞生物学研究：优化控释口服药物递送策略

基本信息

批准号：
12672155
负责人：
YUASA Hiroaki
金额：
$ 2.11万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

It was found in the rat that riboflavin transport in the colon is mediated by a Na^+dependent carrier-mediated transport system similar to one in the small intestine. The transport system in the colon was as efficient as one in the small intestine. It was also found that several tricyclic-type drugs analogous to riboflavin, such as chlorpromazine, specifically inhibit carrier-mediated riboflavin transport in both intestinal sites. Those inhibitors may include competitive substrates that could be transported, though it requires more detailed investigation. Furthermore, the riboflavin transport systems in both intestinal sites seemed to be quite similar in terms of recognition of substrates and inhibitors, though they might not be identical. For some other carrier-mediated transport systems examined, those of D-glucose and bile acids were found to be present in the colon, though far less efficient than the riboflavin transport system. Thus, the riboflavin transport system seemed to be most promising for utilization in oral drug delivery via colon. Drugs designed to fit the riboflavin carriers and as well absorbed from the colon as from the small intestine would be suitable for a sustained-release formulation that is effective even after reaching the colon.Drugs that are metabolized by CYP3A, such as cyclosporine, were found to be significantly metabolized at first-pass in the colon of rats as well as in the small intestine. Thus, in terms of metabolism by CYP3A, delivery via colon would not lead to any further reduction in bioavailability, compared with delivery via small intestine. However, the membrane permeability of cyclosporine, which is restricted by secretory transport by P-glycoprotein, was significantly lower in the colon than in the small intestine. Therefore, for those that undergo CYP3A metabolism and P-glycoprotein secretion, delivery via colon could lead to a reduction in the bioavailability.

在大鼠中发现，核黄素在结肠中的转运是由一个Na^+依赖性载体介导的转运系统介导的，该系统与小肠中的转运系统相似。结肠中的转运系统与小肠中的转运系统一样有效。还发现，几种三环类药物类似于核黄素，如氯丙嗪，特异性抑制载体介导的核黄素在两个肠道部位的转运。这些抑制剂可能包括竞争性底物，可以运输，但它需要更详细的调查。此外，核黄素转运系统在肠道网站似乎是非常相似的识别底物和抑制剂方面，虽然他们可能不相同。对于一些其他载体介导的运输系统检查，D-葡萄糖和胆汁酸被发现存在于结肠中，虽然远不如核黄素运输系统的效率。因此，核黄素转运系统似乎是最有前途的利用口服药物通过结肠输送。设计成适合核黄素载体并且从结肠和小肠吸收良好的药物将适合于即使到达结肠后也有效的缓释制剂。经CYP 3A代谢的药物（如环孢素）被发现在大鼠结肠和小肠的首过中显著代谢。因此，就CYP 3A代谢而言，与经小肠给药相比，经结肠给药不会导致生物利用度进一步降低。然而，环孢霉素的膜渗透性，这是由P-糖蛋白的分泌运输的限制，是显着低于在结肠比在小肠。因此，对于那些经历CYP 3A代谢和P-糖蛋白分泌的药物，通过结肠给药可能导致生物利用度降低。