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Na + 依赖性载体介导的转运系统介导的，类似于小肠中的转运系统。结肠中的运输系统与小肠中的运输系统一样有效。还发现一些类似于核黄素的三环类药物，例如氯丙嗪，可以特异性抑制载体介导的核黄素在两个肠道位点的转运。这些抑制剂可能包括可以运输的竞争性底物，但需要更详细的研究。此外，两个肠道部位的核黄素转运系统在底物和抑制剂的识别方面似乎非常相似，尽管它们可能不相同。对于所检查的其他一些载体介导的运输系统，发现 D-葡萄糖和胆汁酸的运输系统存在于结肠中，尽管其效率远低于核黄素运输系统。因此，核黄素转运系统似乎最有希望用于通过结肠的口服药物递送。设计为适合核黄素载体并且从结肠和小肠吸收一样好的药物将适合缓释制剂，即使在到达结肠后也有效。发现了由 CYP3A 代谢的药物，例如环孢菌素在大鼠结肠和小肠中首过被显着代谢。因此，就 CYP3A 的代谢而言，与通过小肠递送相比，通过结肠递送不会导致生物利用度进一步降低。然而，环孢菌素的膜通透性受到P-糖蛋白分泌转运的限制，在结肠中显着低于在小肠中。因此，对于那些经历 CYP3A 代谢和 P-糖蛋白分泌的人来说，通过结肠递送可能会导致生物利用度降低。