Molecular mechanism of blood-brain barrier transport of drugs.

对形成血脑屏障（BBB）的脑毛细血管内皮细胞（BECEC）中的各种转运系统进行了如下表征：1. β-氨基酸转运系统：β-丙氨酸和牛磺酸等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，该转运机制以氯离子敏感的方式由钠离子梯度激发。本研究以原代培养的牛BCEC为研究对象，通过合成具有不同亲脂性、等电点和分子大小的阳离子衍生肽，并对其底物特异性进行了初步研究，结果表明，BCEC的内吞作用是由β-氨基酸在血脑屏障上的内流和外流所共同调控的。3.对乳酸等一元羧酸转运蛋白进行了分子表征。体外培养细胞和体内BUI研究发现，一元羧酸转运蛋白MCT-1基因在BCEC中表达，并在有机弱酸的血脑屏障转运中发挥重要作用。4.新型喹诺酮类抗菌药物HSR-903在血脑屏障中表达多种脑外排机制，它们是P-糖蛋白和对阴离子敏感的未知转运蛋白。这些外排转运蛋白似乎限制了HSR-903在脑内的分布，从而使其在中枢神经系统的毒性降低，这些研究为BBB的功能提供了新的认识，并暗示了通过关注血脑屏障转运蛋白来控制药物脑内分布的新策略。

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.