Löscher Wolfgang, Potschka Heidrun
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany.
Prog Neurobiol. 2005 May;76(1):22-76. doi: 10.1016/j.pneurobio.2005.04.006.
The blood-brain barrier (BBB) serves as a protective mechanism for the brain by preventing entry of potentially harmful substances from free access to the central nervous system (CNS). Tight junctions present between the brain microvessel endothelial cells form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the barrier properties of the brain capillary endothelial cells. Because of these properties, the BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for drug efflux transporters such as P-glycoprotein (Pgp), multidrug resistance proteins (MRPs) or organic anion transporting polypeptides (OATPs) that are expressed at brain capillary endothelial cells and/or astrocytic end-feet and are key elements of the molecular machinery that confers the special permeability properties to the BBB. The combined action of these carrier systems results in rapid efflux of xenobiotics from the CNS. The objective of this review is to summarize transporter characteristics (cellular localization, specificity, regulation, and potential inhibition) for drug efflux transport systems identified in the BBB and blood-cerebrospinal fluid (CSF) barrier. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on brain access of therapeutic drugs also are described and critically discussed. The potential impact of efflux transport on the pharmacodynamics of agents acting in the CNS is illustrated. Furthermore, the current knowledge about drug efflux transporters as a major determinant of multidrug resistance of brain diseases such as epilepsy is reviewed. Finally, we summarize strategies for modulating or by-passing drug efflux transporters at the BBB as novel therapeutic approaches to drug-resistant brain diseases.
血脑屏障（BBB）通过阻止潜在有害物质自由进入中枢神经系统（CNS），为大脑提供保护机制。脑微血管内皮细胞之间存在的紧密连接形成了一个扩散屏障，可选择性地阻止大多数血液传播物质进入大脑。星形胶质细胞的终足紧密包裹血管壁，对于诱导和维持脑毛细血管内皮细胞的屏障特性似乎至关重要。由于这些特性，血脑屏障仅允许低分子量亲脂性化合物通过被动扩散进入。然而，许多亲脂性药物在脑内的摄取量可忽略不计。它们是药物外排转运蛋白的底物，如P-糖蛋白（Pgp）、多药耐药蛋白（MRP）或有机阴离子转运多肽（OATP），这些转运蛋白在脑毛细血管内皮细胞和/或星形胶质细胞终足中表达，是赋予血脑屏障特殊通透性特性的分子机制的关键要素。这些载体系统的联合作用导致外源性物质从CNS快速流出。本综述的目的是总结血脑屏障和血脑脊液（CSF）屏障中已确定的药物外排转运系统的转运体特征（细胞定位、特异性、调节和潜在抑制）。还描述并批判性地讨论了用于确定或预测外排转运对治疗药物脑内摄取影响的各种实验方法。阐述了外排转运对作用于CNS的药物药效学的潜在影响。此外，还综述了关于药物外排转运蛋白作为癫痫等脑部疾病多药耐药主要决定因素的现有知识。最后，我们总结了调节或绕过血脑屏障处药物外排转运蛋白的策略，作为耐药性脑部疾病的新型治疗方法。
