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Quantitative Evaluation of Blood-Brain Barrier Efflux Transport of Drugs

药物血脑屏障外流转运的定量评价

基本信息

批准号：
07672469
负责人：
DEGUCHI Yoshiharu
金额：
$ 1.02万
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：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Clarification of the brain distribution of centrally acting pharmaceuticals after systemic administration is important to better understanding their pharmacological effects in the central nervous system. As a rule, the drug concentration in the brain has been known to be regulated by several factors. In particular, the equilibration between blood and brain depends dominantly on the balance of influx and efflux transports across the blood-brain barrier (BBB). However, there are few reports about rate and role of the BBB efflux transport of drugs. Therefore, this study was performed to evaluate quantitatively the influx and efflux transports across the BBB of acidic drugs, using in vivo microdialysis, in situ brain perfusion techniques, intravenous and intra-interstitial-fluid administration method. Probenecid and salicylate were selected as model compounds. The brain interstitial fluid-, cerebrospinal fluid-, and brain tissue-to-plasma unbound concentration ratios of probenecid and sali … More cylate at steady state were less than unity, suggesting restricted distribution in the brain. An uphill concentration gradient from ISF to plasma and a downhill concentration gradient from CSF to ISF,were observed. Kinetic analysis revealed that the efflux clearances of these drugs from brain ISF to plasma were significantly greater than the influx clearances from plasma to brain. The efflux transport of probenecid was significantly inhibited by treatment with N-ethylmaleimide, a sulfhydryl-modifying agent, and salicylate (3.7mM) and benzoate (3.6 mM) which are accepted as substrates of the monocarboxylic acid transport system. On the other hand, p-aminohippuric acid and choline did not produce the inhibition effect. Moreover, the efflux transport of salicylate was inhibited by probenecid (1.4 mM) and benzoate (3.6 mM). These date suggest that the restricted distribution of probenecid and salicylate in the brain may be ascribed to efficient efflux from the brain ISF,which may be regulated by the MCT system at the BBB. Less

阐明中枢作用药物在全身给药后的脑分布对更好地了解其在中枢神经系统中的药理作用具有重要意义。一般来说，大脑中的药物浓度受到几个因素的调节。特别是，血液和大脑之间的平衡主要取决于通过血脑屏障（BBB）的流入和流出运输的平衡。然而，关于血脑屏障外排转运药物的速率和作用的报道很少。因此，本研究采用体内微透析、脑原位灌注技术、静脉和间质液给药方法，定量评估酸性药物在血脑屏障内的内流和外排转运。以Probenecid和水杨酸酯为模型化合物。脑组织间质液-、脑脊液-、脑组织与血浆的非结合浓度比，稳定状态下环酸盐含量大于1，提示其在脑内分布受限。观察到从ISF到血浆的浓度梯度呈上坡，从CSF到ISF的浓度梯度呈下坡。动力学分析显示，这些药物从脑ISF到血浆的外排清除率明显大于从血浆到脑的内流清除率。巯基改性剂n -乙基马来酰亚胺和水杨酸酯（3.7mM）和苯甲酸酯（3.6 mM）作为单羧酸转运系统的底物，显著抑制了丙烯酸酯的外排转运。而对氨基马尿酸和胆碱则不产生抑制作用。此外，probenecid （1.4 mM）和苯甲酸酯（3.6 mM）可抑制水杨酸酯的外排转运。这些数据表明，probenecid和水杨酸盐在大脑中的有限分布可能归因于大脑ISF的有效外排，这可能由血脑屏障的MCT系统调节。少