Molecular design of drug efflux system modulator at blood-brain barrier

血脑屏障药物流出系统调节剂的分子设计

基本信息

批准号：
08457619
负责人：
TERASAKI Tetsuya
金额：
$ 4.8万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457619/
关键词：
blood-brain barrier brain membrane transport efflux transport drug delivery brain efflux index method organic anion transport P-glycoprotein 脳毛細血管解毒薬物排出輸送脳排出指標

项目摘要

The blood-brain barrier (BBB) influx rate of BECEF-AM (Mw : 809) was determined and was very similar to that of predicted from the octanol-water partition coefficient. Quinidine (Mw : 324) was pumped out from the brain to the circulating blood via mdrla gene product at the BBB.These results suggest the lack of molecular threshold at the BBB.We have developed the brain efflux index (BEI) method to determine the efflux transport rate of drugs at the BBB.The restricted brain distribution of 3'-Azido-3'-deoxythymidine (AZT) and 2', 3'-dideoxyinosine (DDl) was analyzed using the distributed model, suggesting that both drugs are significantly effluxed from the brain via the BBB.The BBB efflux of AZT and DDI was characterized to transport via the organic anion transport system by the BEI method. Para-aminohippuric acid (PAH), an organic anion, was used to reveal the organic anion efflux transport system at the BBB.PAH was selectively effluxed from the brain to the blood. Saturable efflux of PAH was shown, suggesting the presence of the carrier-madia organic anion transport system at the BBB.B -Alanine and quinolone antibiotics were also suggested to be pumped out from the brain at the BBB via each different carrier-mediated transport system. Interestingly, in vivo evidences were obtained to suggest that the neurotranmitters such as GABA and acidic amino acid were effluxed at the BBB.In conclusion, as shown in the above results, several efflux transport systems, including P-glycoprotein, play an important role for the regulation of normal cerebral function. Based on these findings, we have proposed a new strategy for the drug design that the lack of the affinity to the efflux transport system at the BBB would be efficient to increase the apparent influx rate of the drug to the brain.

确定了BECEF-AM（MW：809）的血脑屏障（BBB）涌入率，并且与辛烷值 - 水分分区系数的预测非常相似。在BBB处通过MDRLA基因产物从大脑中抽出奎尼丁（MW：324）。这些结果表明，BBB的分子阈值缺乏分子阈值。我们已经开发了大脑外排指数（BEI）的方法来确定BBB的外排运输速率A。使用分布式模型分析了2'，3'-二维氨酸（DDL），这表明两种药物都通过BBB显着从大脑中排出。AZT和DDI的BBB外排是通过BEI方法通过有机阴离子传输系统通过有机阴离子传输的。一种有机阴离子帕拉 - 氨基硫酸（PAH）用于揭示BBB的有机阴离子外排运输系统。显示了PAH的饱和外排，这表明在BBB.B.B-丙氨酸和喹诺酮抗生素上存在载体 - 麦迪亚有机阴离子传输系统，并建议通过每个不同的载体介导的运输系统从BBB的大脑中抽出大脑。有趣的是，获得了体内证据，表明在BBB上将神经夹（例如GABA和酸性氨基酸）排出。结论，如上所述，几种外排运输系统，包括P-糖蛋白在内，在正常脑功能的调节中起重要作用。根据这些发现，我们提出了一种新的药物设计策略，即缺乏对BBB的外排运输系统的亲和力将有效地提高药物对大脑的明显涌入率。