Drug deliver by utilization of tissue specific transportes.

通过基因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膜转运的各种转运蛋白。主要研究结果如下：1.对新的转运蛋白家族OCTNs进行分子克隆，并通过转染HEK 293细胞分析其转运功能。人和小鼠OCTN 2以钠依赖性方式运输生理上重要的肉毒碱。表现出全身性肉毒碱缺乏（SCD）综合征的JVS小鼠在OCTN 2基因中存在突变，从而丧失肉毒碱转运功能。此外，在显示SCD综合征的患者中鉴定出OCTN 2基因的各种突变。根据这些结果，阐明了OCTN 2是生理学上重要的卡米丁转运蛋白，并且其突变导致SCD。有趣的是，OCTN 2及其亚型OCTN 1以不依赖钠的方式转运有机阳离子。因此，OCTNs是一种独特的转运蛋白，通过不同的机制转运肉毒碱和有机阳离子，具有多功能性.进行了血脑屏障（BBB）处单羧酸转运蛋白的分子表征。一元羧酸转运蛋白MCT-1基因在血脑屏障表达，体外培养细胞和体内研究发现其在有机弱酸的转运中起重要作用.发现新喹诺酮类抗菌剂的多种外排机制在BBB表达。它们是对阴离子化合物敏感的P-糖蛋白和未知转运蛋白。这些多外排转运蛋白似乎限制了喹诺酮类药物和其他药物的脑分布，导致其在中枢神经系统中的分布较低，这些研究为膜转运蛋白的重要性提供了新的见解，并通过关注转运蛋白在各种组织中的功能来控制药物的处置提供了新的策略。

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.