Wang Q, Yang H, Miller D W, Elmquist W F
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
Biochem Biophys Res Commun. 1995 Jun 26;211(3):719-26. doi: 10.1006/bbrc.1995.1872.
The p-glycoprotein is a transmembrane efflux transporter found on the luminal side of the capillary endothelial cells that comprise the blood-brain barrier. This study examined the effect of a p-glycoprotein inhibitor, cyclosporin A, on the distribution to the brain of a p-glycoprotein substrate, rhodamine-123, in freely moving rats using intracerebral microdialysis coupled with on-line HPLC analysis. Results from crossover experiments show that the coadministration of cyclosporin A significantly increased the distribution of rhodamine-123 to the brain. The plasma disposition of rhodamine-123 was unchanged by cyclosporin A, indicating that the change in brain exposure was mediated by a process at the level of the blood-brain barrier, possibly by inhibition of the p-glycoprotein efflux transporter. This finding suggests a functional activity of the p-glycoprotein in the blood-brain barrier and validates an in vivo model to examine the role of this transporter in the brain distribution of drugs.
P-糖蛋白是一种跨膜外排转运体，存在于构成血脑屏障的毛细血管内皮细胞的管腔侧。本研究使用脑内微透析结合在线高效液相色谱分析，检测了P-糖蛋白抑制剂环孢素A对P-糖蛋白底物罗丹明-123在自由活动大鼠脑内分布的影响。交叉实验结果表明，联合给予环孢素A显著增加了罗丹明-123在脑内的分布。环孢素A对罗丹明-123的血浆处置无影响，表明脑内暴露的变化是由血脑屏障水平的过程介导的，可能是通过抑制P-糖蛋白外排转运体。这一发现提示了P-糖蛋白在血脑屏障中的功能活性，并验证了一种体内模型，用于研究该转运体在药物脑内分布中的作用。
