Development of Novel CNS Drug Delivery System by Regulating the BBB Efflux Transport System

越来越多的证据表明，血脑屏障(BBB)中的药物外排泵如P-糖蛋白被许多药物从脑内主动挤出到血液循环中，导致药物在脑内的分布有限。本研究的目的是寻找能识别血脑屏障外排转运系统的药物，并开发调节血脑屏障外排系统的新型给药系统。1)急性淋巴细胞白血病患者持续应用6-巯基嘌呤(6-MP)易导致中枢神经系统复发。这可能是由于6-MP在脑内的分布受限所致。因此，对6-MP的血脑屏障转运进行了研究。结果发现，6-MP脑内分布受限可能归因于从脑内主动排出，可能是通过有机阴离子转运系统和单羧酸转运系统。这项研究还表明，联合应用像丙磺舒这样的转运抑制剂可能会改善这种受限的6-MP在大脑中的分布。2)最近有报道称非类固醇抗炎药(NSAIDs)对阿尔茨海默病有效。然而，非类固醇抗炎药在大脑中的分布非常有限。因此，本研究旨在探讨新合成的酮洛芬甘油酯前体药物(KT)是否能促进KT的脑内转运。DAKG可促进KT从血侧向脑内的摄取。另外，丙磺舒与DAKG合用通过抑制DAKG代谢的KT在脑内的外流转运，显著改善了KT的脑内转运，为中枢神经系统药物的发现和治疗提供了有意义的信息。

There are increasing evidences that the drug efflux pump like P-glycoprotein in the blood- brain barrier (BBB) is actively extruded many drugs from brain to blood circulation, resulting in the limited distribution to the brain. The goal of this research was to find drugs that is recognized by the efflux transport system in the BBB, and to develop the novel drug delivery system in which the BBB efflux system is being regulated. 1) Patients with acute lymphoblastic leukemia who continuously receive 6-mercaptopurine (6-MP) are often brought about the CNS relapse. This may be caused by the restricted distribution of 6-MP in the brain. Therefore, the BBB transport of 6-MP was examined. As a result, it was found that the restricted 6-MP brain distribution may be ascribe to the active extrusion from the brain, possibly via the organic anion transport system and the monocarboxylic acid transport system. This study also suggests that the coadministration of a transport inhibitor like probenecid may improve this restricted 6-MP distribution in the brain. 2) Recently, it has been reported that nonsteroidal antiinflammatory drugs (NSAIDs) were effective to Alzheimer's disease. However, the distribution of NSAIDs into the brain is very limited. Therefore, in this study, it was examined whether a newly synthesized glyceride prodrug of ketoprofen (KT) improve the brain delivery of KT.DAKG could improve the brain uptake of KT from blood side to brain. In addition, the coadministration of probenecid with DAKG significantly improve the brain delivery of KT by inhibiting the efflux transport of KT which was metabolized from DAKG in the brain.The findings obtained here will provide significant information for CNS drug discovery and CNS drug therapy.