Molecular mechanism of blood-brain barrier transport of drugs.

脑毛细血管内皮细胞(BECEC)上形成血脑屏障(BBB)的转运系统有以下几种：1.β-氨基酸转运系统：β-丙氨酸、牛磺酸等β-氨基酸通过特定的载体介导的转运机制跨血脑屏障转运，这种转运机制受钠离子梯度以氯离子敏感的方式提供能量。在BCEC的腔膜和腔膜上发现了转运蛋白的功能，表明β-氨基酸跨血脑屏障的内流和外流都受到这种转运蛋白的调节(S)。2.利用原代培养的牛BCEC进一步研究了吸附介导的内吞作用的底物特异性。通过新合成不同亲脂性、等电点和分子大小的阳离子衍生多肽，推测了其作用机制的最佳结构。3.对乳酸等一元羧酸的转运蛋白进行了分子表征。单羧酸转运蛋白MCT-1基因在BCEC中表达，体外培养细胞和体内BUL研究发现MCT-1基因在血脑屏障的有机弱酸转运中起重要作用。4.新型喹诺酮类抗菌药物HSR-903的多种脑外排机制被发现在BCEC中有功能表达，它们是P-糖蛋白，对阴离子化合物敏感。这些多个外流转运体似乎限制了HSR-903的脑分布，导致对中枢神经系统的低毒性。这些研究为了解血脑屏障的功能提供了新的见解，并暗示了通过关注血脑屏障上的转运体来控制药物脑分布的新策略。

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.