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

测定了BECEF-AM（Mw：809）的血脑屏障（BBB）内流率，结果与根据辛醇-水分配系数预测的内流率非常相似。奎尼丁（分子量：324）在血脑屏障处通过mdr 1a基因产物从脑泵出进入循环血液。这些结果表明血脑屏障处缺乏分子阈值。我们发展了脑外排指数（BEI）方法来测定药物在血脑屏障处的外排转运速率。用分布模型分析了3 '-二脱氧肌苷（DD 1）的外排，结果表明两种药物均经血脑屏障（BBB）外排。用BEI方法研究了AZT和DD 1的BBB外排，结果表明AZT和DD 1均经有机阴离子转运系统转运。对氨基马尿酸（PAH）是一种有机阴离子，它被选择性地从脑外排到血液中，从而揭示了血脑屏障上的有机阴离子外排转运系统。PAH的饱和外排表明，在BB B存在载体介导的有机阴离子转运系统。B -丙氨酸和喹诺酮类抗生素也被认为是通过各种不同的载体介导的转运系统从BB B脑中泵出的。有趣的是，在体内的证据表明，神经递质，如GABA和酸性氨基酸在BBB的外排。总之，在上述结果中所示，包括P-糖蛋白，几个外排转运系统，在正常的脑功能的调节中发挥重要作用。基于这些发现，我们提出了一种新的药物设计策略，即在BBB处缺乏对外排转运系统的亲和力将有效地增加药物向脑的表观内流速率。

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.