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

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。结肠中的运输系统和小肠中的运输系统一样高效。研究还发现，几种类似核黄素的三环类药物，如氯丙嗪，可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可以运输的竞争性底物，尽管这需要更详细的研究。此外，两个肠道部位的核黄素转运系统在识别底物和抑制剂方面似乎非常相似，尽管它们可能不完全相同。对于其他一些载体介导的运输系统，d -葡萄糖和胆汁酸的运输系统被发现存在于结肠中，尽管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经结肠口服给药。设计适合核黄素载体的药物，并从结肠和小肠吸收，将适合于一种缓释制剂，即使在到达结肠后也有效。被CYP3A代谢的药物，如环孢素，在大鼠的结肠和小肠中首次被显著代谢。因此，就CYP3A代谢而言，经结肠给药与经小肠给药相比，不会导致生物利用度进一步降低。然而，环孢素受p糖蛋白分泌运输的限制，其在结肠中的膜通透性明显低于小肠。因此，对于那些经历CYP3A代谢和p糖蛋白分泌的人来说，经结肠给药可能导致生物利用度降低。

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.