Drug deliver by utilization of tissue specific transportes.

通过基因的分子克隆和基因表达系统的功能分析，阐明了介导药物和生理化合物的膜转运的各种转运体。主要研究结果如下：1.克隆了新的转运蛋白家族OCTN，并将该基因导入HEK293细胞，分析了其转运蛋白的功能。人和小鼠OCTN2以钠依赖的方式转运生理上重要的肉碱。表现为全身性肉碱缺乏综合征的JVS小鼠OCTN2基因发生突变，肉碱转运功能丧失。此外，在表现为SCD综合征的患者中发现了OCTN2基因的各种突变。这些结果表明，OCTN2是一种重要的生理转运蛋白，它的突变导致了SCD。有趣的是，OCTN2及其异构体OCTN1以不依赖于钠的方式运输有机阳离子。因此，OCTN是独特的转运体，通过在不同的机制中转运肉碱和有机阳离子而具有多功能。对一元羧酸转运体在血脑屏障(BBB)的分子特征进行了研究。单羧酸转运蛋白MCT-1基因在血脑屏障中表达，在体外培养细胞和体内研究中发现，MCT-1在有机弱酸的转运中起重要作用。新的喹诺酮类抗菌药物的多种外排机制被发现表达在血脑屏障上。它们是P-糖蛋白和对阴离子化合物敏感的未知转运蛋白。这些多个外排转运体似乎限制了喹诺酮类药物和其他药物在大脑中的分布，导致中枢神经系统的低分布。这些研究为了解膜转运体的意义提供了新的见解，并提供了通过关注存在于各种组织中的转运体功能来控制药物处置的新策略。

Various transporters that mediate membrane transport of drugs as well as physiological compounds were clarified by molecular cloning of the genes and their functional analysis by gene expression systems. The obtained results are as follows :1. Novel transporter family OCTNs were molecularly cloned and their transport functions were analyzed by transfection of the gene to HEK293 cells. Human and mouse OCTN2 transported physiologically important carnitine in a sodium dependent manner. JVS mice that show systemic carnitine deficiency(SCD) syndrome had a mutation in OCTN2 gene with loss of carnitine transport function. Furthermore, various mutations in OCTN2 gene were identified in patients who show the SCD syndrome. From these results, it was clarified that OCTN2 is a physiologically important camitine transporter and its mutation leads to the SCD. Interestingly, OCTN2 and its isoform OCTN1 transported organic cations in a sodium independent manner. Accordingly, OCTNs are unique transporters which have are multifunctionality by transporting carnitine and organic cations in the distinct mechanisms.2. Molecular characterization of the transporter for monocarboxylic acids at the blood-brain barrier (BBB) was performed. Monocarboxylic acid transporter MCT-1 gene was expressed at the BBB and was found to play important role in the transport of organic weak acids by the in vitro cultured cells and in vivo studies.3. Multiple efflux mechanisms for new quinolone antibacterial agent were found to be expressed at the BBB. They are P-glycoprotein and unknown transporters sensitive to anionic compounds. These multiple efflux transporters seem to restrict the brain distribution of quinolones and other drugs, resulting in a low distribution into the central nervous system.These lines of studies provide new insight of the siginificance of membrane transporters and new strategy to control disposition of drugs by focusing on the transporters function present in various tissues.