Drug Delivery based on Multiplicity of Various Membrane Transporters

基于多种膜转运蛋白的药物递送

基本信息

批准号：
12307057
负责人：
TSUJI Akira
金额：
$ 21.13万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
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

The author' s research on transporter-mediated pharmacokinetics focuses on the molecular functional characteristics of drug transporters including oligopeptide transporter, monocarboxylic acid transporter, anion transporter, organic cation transporters, organic cation/carnitine transporters (OCTNs) and the ATP-binding cassette transporters P-glycoprotein and MRP2. We have successfully demonstrated that the transporters play important roles in the influxes and/or effluxes of drugs in intestinal and renal epithelial cells, hepatocytes and brain capillary endothelial cells that form the blood-brain barrier. In the systemic carnitine deficiency (SCD) phenotype mouse model, juvenile visceral seatosis (jvs) mouse, a mutation in the OCTN2 gene was found. Furthermore, several types of mutation in human SCD patients were found, demonstrating that OCTN2 is a physiologically important carnitine transporter. OCTNs transport not only carnitine but also various organic cationic drugs in a sodium-independent manner. It is suggested that OCTNs are multifunctional transporters for the uptake of carnitine into tissue cells and at the same time for the elimination of intracellular organic cationic drugs. In this research term, novel cDNA of organic anion transporters i.e., OATP-B, OATP-D and OATP-E have been isolated and functionally characterized. Furthermore, single nucleotide polymorphism of OATP-B, OATP-C and OCTN2 in the Japanese population was analyzed. Although more data should be collected, such information will enable us to establish ultimate drug delivery system.

作者对转运蛋白介导的药代动力学的研究重点介绍了药物转运蛋白的分子功能特性，包括寡肽转运蛋白，单羧酸转运蛋白，阴离子转运蛋白，有机阳离子转运蛋白，有机阳离子/肉碱转运蛋白（coctns）和ATP绑扎cassette cassette Transporters P - 糖蛋白和MRP2。我们已经成功地证明了转运蛋白在肠道和肾上皮细胞，肝细胞以及脑毛细血管内皮细胞中的药物的流入和/或外排起重要作用，形成了血脑屏障。在全身性肉碱缺乏症（SCD）表型小鼠模型中，发现了octn2基因中的突变。此外，发现了人类SCD患者的几种突变，表明octn2是一种重要的肉碱转运蛋白。八个不仅以钠的方式运输肉碱，而且以钠独立的方式运输各种有机阳离子药物。据建议，八个是多功能转运蛋白，可用于摄取肉碱到组织细胞，同时消除细胞内有机阳离子药物。在本研究术语中，有机阴离子转运蛋白的新型cDNA，即OATP-B，OATP-D和OATP-E已被分离并在功能上表征。此外，分析了日本人群中OATP-B，OATP-C和OCTN2的单核苷酸多态性。尽管应该收集更多数据，但这些信息将使我们能够建立最终的药物输送系统。