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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.

笔者在转运体介导的药代动力学方面的研究重点是药物转运体的分子功能特征，包括寡肽转运体、单羧酸转运体、阴离子转运体、有机阳离子转运体、有机阳离子/肉碱转运体（OCTNs）和atp结合盒转运体p -糖蛋白和MRP2。我们已经成功地证明了转运蛋白在形成血脑屏障的肠和肾上皮细胞、肝细胞和脑毛细血管内皮细胞的药物流入和/或流出中发挥重要作用。在系统性肉毒碱缺乏症（SCD）表型小鼠模型中，发现了OCTN2基因突变。此外，在人类SCD患者中发现了几种类型的突变，表明OCTN2是生理上重要的肉碱转运蛋白。octn不仅能以不依赖钠的方式转运肉碱，还能转运多种有机阳离子药物。这表明octn是一种多功能转运体，既能将肉碱摄取到组织细胞中，同时又能消除细胞内的有机阳离子药物。本研究从有机阴离子转运体otp - b、otp - d和otp - e中分离出新的cDNA，并对其进行了功能表征。进一步分析了ooatp - b、ooatp - c和OCTN2在日本人群中的单核苷酸多态性。虽然需要收集更多的数据，但这些信息将使我们能够建立最终的给药系统。