The Application of 'Passport' and 'Gateway' Proteins to the Absorption, Distribution, Excretion and Delivery of Drugs

药物转运体被认为是药物吸收、分布、排泄和释放的重要因素。因此，本课题研究了药物转运蛋白在人体内的“通行证”和“门户”功能，旨在阐明底物识别机制，构建药物开发中的高通量筛选体系。转运蛋白可以作为代谢酶的假说在该领域是一个新的假说，用蛋白脂质体进行验证将为开发口服有效的多肽类药物提供有益的发现。此外，OCTN2被证明参与了肉碱的肠道吸收。这一发现表明，PEPT1和PCTN2等内流转运体在药物的肠道吸收中也起着重要作用，进一步深入的体内研究将有助于提高口服给药的生物利用度。此外，蛋白质-蛋白质相互作用的研究也为药物转运蛋白的调控机制提供了信息。PDZ-K1是一种膜支架蛋白，用于调节或修饰药物转运蛋白的表达、稳定性和活性。因此，有人认为转运蛋白是通过与膜支架蛋白的相互作用来进行生理调控的。从这个项目中获得的信息导致了高通量筛选的建立。非洲爪哇卵母细胞系统表达转运蛋白和膜支架蛋白。

Drug transporters are thought to be an important factor in drug absorption, distribution, excretion and delivery. Therefore, in this project, we studied drug transporters that act as the 'Passport' and 'Gateway' proteins in human body, and aimed to elucidate the mechanisms of substrate recognition and construct a system for high-through-put screening in drug developments.As the harvests of this project, the hydrolysis function of intestinal oligopeptide transporter, PEPT1, was suggested. The hypothesis that transporters could act as metabolic enzymes is novel one in this field, and verifying with proteoliposomes will provide beneficial findings to develop the orally effective peptide-like drugs. Additionally, Octn2 was shown to be involved in the intestinal absorption of carnitine. This finding suggested that influx transporters, such as PEPT1 and PCTN2, also have important roles in the intestinal absorption of drugs, and that further intensive in vivo researches will be lead to the improvement of bioavailability in oral administrations. Furthermore, study on protein-protein interaction provided the information about regulation mechanisms for drug transporter. PDZ-K1, a membrane scaffold protein was clarified, to regulate or modify the expression, stability and activity of drug transporters. Therefore, it was suggested that transporters are physiologically governed via interactions with membrane scaffold proteins. Information obtained from this project lead to build up high-through-put screening. Xenopus laevis oocytes system expressed with transporters and membrane scaffold protein.