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

通过调节 BBB 外排运输系统开发新型 CNS 药物输送系统

• 批准号: 09672332
• 负责人: DEGUCHI Yoshiharu
• 金额: $ 1.79万
• 依托单位: University of Shizuoka
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672332/
• 关键词: anion transport system; BBB efflux transport; Alzheimer's disease; ketoprofen; 6-mercaptopurine; improvement of CNS delivery; probenecid; prodrug; 血液脳関門; 排出輸送; モノカルボン酸輸送系; 脳移行性改善; ペプチド性薬物; アセチルコリンエステラーゼ阻害薬; 脳送達法; 脳内代謝; グリセロール

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.

越来越多的证据表明，血脑屏障（blood-brain barrier，BBB）中的P-糖蛋白（P-glycoprotein，P-糖蛋白）等药物外排泵能将药物从脑内主动排到血液循环中，从而限制药物在脑内的分布。本研究的目的是寻找能够被血脑屏障外排转运系统识别的药物，并开发能够调节血脑屏障外排转运系统的新型给药系统。1)急性淋巴细胞白血病患者持续接受6-巯基嘌呤（6-MP）治疗常导致中枢神经系统复发。这可能是由于6-MP在大脑中的分布受限所致。因此，检查了6-MP的BBB转运。结果表明，6-MP脑内分布受限可能是由于脑内的主动排出所致，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，运输抑制剂如丙磺舒的共同管理可能会改善这种限制6-MP在大脑中的分布。2)近年来，非甾体类抗炎药（NSAIDs）对阿尔茨海默病的治疗有一定的疗效。然而，NSAID在大脑中的分布非常有限。因此，本研究考察了新合成的酮洛芬（KT）甘油酯前体药物是否能改善KT的脑内转运。DAKG能改善KT从血侧到脑的脑摄取。此外，丙磺舒与DAKG合用可抑制DAKG代谢的KT在脑内的外排转运，从而显著提高KT的脑内转运，为中枢神经系统药物的发现和治疗提供了重要的信息。

项目成果

Deguchi, Y.et al.: "Brain Distribution of 6-Mercaptopurine Regulated by the Efflux Transport System in the Blood-Brain Barrier" J.Pharmacol.Exp.Ther.(in press). (1999)

Deguchi, Y.et al.：“血脑屏障中的外排转运系统调节 6-巯基嘌呤的脑分布”J.Pharmacol.Exp.Ther.（出版中）。

Hayashi,H., Deguchi,Y.et al.: "An Attempt to Develop New CNS Pharamaceuticals against Alzheimer's Disease:Improvement of Brain Delivery of NSAIDs by〜." Progress in Drug Deliv.System.6. 53-61 (1997)

Hayashi, H., Deguchi, Y. 等人：“开发抗阿尔茨海默病的新中枢神经系统药物的尝试：通过〜改善非甾体抗炎药的脑递送。药物递送系统的进展 53-61 (1997)。