Tamai I, Tsuji A
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan.
J Pharm Sci. 2000 Nov;89(11):1371-88. doi: 10.1002/1520-6017(200011)89:11<1371::aid-jps1>3.0.co;2-d.
Drug distribution into the brain is strictly regulated by the presence of the blood-brain barrier (BBB) that is formed by brain capillary endothelial cells. Since the endothelial cells are connected to each other by tight junctions and lack pores and/or fenestrations, compounds must cross the membranes of the cells to enter the brain from the bloodstream. Therefore, hydrophilic compounds cannot cross the barrier in the absence of specific mechanisms such as membrane transporters or endocytosis. So, for efficient supply of hydrophilic nutrients, the BBB is equipped with membrane transport systems and some of those transporter proteins have been shown to accept drug molecules and transport them into brain. In the present review, we describe mainly the transporters that are involved in drug transfer across the BBB and have been molecularly identified. The transport systems described include transporters for amino acids, monocarboxylic acids, organic cations, hexoses, nucleosides, and peptides. Most of these transporters function in the direction of influx from blood to brain; the presence of efflux transporters from brain to blood has also been demonstrated, including P-glycoprotein, MRPs, and other unknown transporters. These efflux transporters seem to be functional for detoxication and/or prevention of nonessential compounds from entering the brain. Various drugs are transported out of the brain via such efflux transporters, resulting in the decrease of CNS side effects for drugs that have pharmacological targets in peripheral tissues or in the reduction of efficacy in CNS because of the lower delivery by efflux transport. To identify the transporters functional at the BBB and to examine the possible involvement of them in drug transports by molecular and physiological approaches will provide a rational basis for controlling drug distribution to the brain.
药物进入大脑受到血脑屏障（BBB）的严格调控，血脑屏障由脑毛细血管内皮细胞形成。由于内皮细胞通过紧密连接相互连接，且缺乏孔隙和/或窗孔，化合物必须穿过细胞的膜才能从血液进入大脑。因此，在没有诸如膜转运蛋白或内吞作用等特定机制的情况下，亲水性化合物无法穿过该屏障。所以，为了有效地供应亲水性营养物质，血脑屏障配备了膜转运系统，并且已经证明其中一些转运蛋白能够接受药物分子并将它们转运到大脑中。在本综述中，我们主要描述参与药物跨血脑屏障转运且已被分子鉴定的转运蛋白。所描述的转运系统包括氨基酸、单羧酸、有机阳离子、己糖、核苷和肽的转运蛋白。这些转运蛋白中的大多数在从血液到大脑的流入方向上起作用；也已经证明存在从大脑到血液的外排转运蛋白，包括P-糖蛋白、多药耐药相关蛋白（MRPs）和其他未知的转运蛋白。这些外排转运蛋白似乎具有解毒功能和/或防止非必需化合物进入大脑。各种药物通过这种外排转运蛋白被转运出大脑，导致在外周组织中有药理学靶点的药物的中枢神经系统副作用减少，或者由于外排转运导致药物在中枢神经系统中的递送降低而使疗效降低。通过分子和生理学方法鉴定在血脑屏障处起作用的转运蛋白并研究它们可能参与药物转运的情况，将为控制药物向大脑的分布提供合理依据。
