Molecular mechanism of blood-brain barrier transport of drugs.

形成血脑屏障（BBB）的脑毛细血管内皮细胞（BECEC）所配备的各种运输系统具有以下特点：1。-氨基酸运输系统：-氨基酸如-丙氨酸和-牛磺酸通过特定的载体介导的运输机制通过血脑屏障运输，该机制由钠离子梯度以氯离子敏感的方式激活。转运蛋白的功能在BCEC的管腔膜和管腔膜上都被发现，表明β -氨基酸在血脑屏障上的内流和外排都受到这种转运蛋白的调节(s)。利用原代培养的牛BCEC进一步研究了吸附介导的血脑屏障内吞作用的底物特异性。通过新合成的具有不同亲脂性、等电点和分子大小的阳离子衍生多肽，推测了其机理的最佳结构。对乳酸等单羧酸的转运体进行了分子表征。单羧酸转运蛋白MCT-1基因在血脑屏障中表达，体外培养细胞和体内研究发现MCT-1基因在血脑屏障有机弱酸转运中发挥重要功能。新型喹诺酮类抗菌剂HSR-903脑外排机制在血脑屏障处功能表达。它们是p糖蛋白和对阴离子化合物敏感的未知转运蛋白。这些多种外排转运体似乎限制了HSR-903在大脑中的分布，导致其在中枢神经系统中的毒性较低。这些研究为血脑屏障的功能提供了新的认识，并为通过关注血脑屏障转运蛋白来控制药物在脑内的分布提供了新的策略。

Various transport systems equipped in brain capillary endothelial cells (BECEC) that form blood-brain barrier (BBB) were characterized as follows :1.beta-amino acid transport system : beta-amino acids such as beta-alanine and taurine were transported across the blood-brain barrier by specific carrier-mediated transport mechanisms that is energized by sodium ion gradient in a chloride ion sensitive manner. The transporter function was found bcth at the luminal and abluminal membranes of BCEC, indicating that both of influx and efflux of beta-amino acids across the BBB are regulated such transporter(s).2.Substrate specificity of adsorptive-mediated endocytosis at the BBB was further investigated using primary cultured bovine BCEC.By newly synthesizing cationic-derived peptide with various lipophilicity, isoelectric point and molecular size, the optimal structure for the mechanism was speculated.3.Molecular characterization of the transporter for monocarboxylic acids such as lactic acid has been performed. Monocarboxylic acid transporter MCT-1 gene was expressed in the BCEC and was found to functionally play important role in transport of organic weak acids at the BBB by the in vitro cultured cells and in vivo BUl studies.4.Multiple brain efflux mechanisms for new quinolone antibacterial agent, HSR-903 were found to be functionally expressed at the BBB.They are P-glycoprotein and unknown transporter sensitive to anionic compounds. These multiple efflux transporters seem to restrict brain distribution of HSR-903, resulting in a low toxicity in the central nervous system.These lines of studies provide new insight of the function of BBB and imply new strategy to control brain distribution of drugs by focusing on the transporters functioning at the blood-brain barrier.