Quantitative Evaluation of Blood-Brain Barrier Efflux Transport of Drugs

阐明中枢作用药物在全身给药后的脑分布对于更好地理解其在中枢神经系统中的药理作用是重要的。通常，已知脑中的药物浓度受几个因素调节。特别地，血液和脑之间的平衡主要取决于穿过血脑屏障（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，本研究采用在体微透析、原位脑灌注技术、静脉和间质液给药方法，定量评价酸性药物通过BBB的流入和流出转运。选择丙磺舒和水杨酸作为模型化合物。丙磺舒和sali在脑间质液、脑脊液和脑组织中的血浆游离浓度比 ...更多信息 在稳态时，cylate小于1，表明在脑中的分布受限。观察到从ISF到血浆的上坡浓度梯度和从CSF到ISF的下坡浓度梯度。动力学分析表明，这些药物从脑ISF到血浆的流出清除率显著大于从血浆到脑的流入清除率。丙磺舒的外排转运显着抑制治疗与N-乙基马来酰亚胺，巯基修饰剂，水杨酸盐（3.7 mM）和苯甲酸盐（3.6 mM），这是接受作为底物的单羧酸运输系统。而对氨基马尿酸和胆碱则不产生抑制作用。此外，外排转运水杨酸抑制丙磺舒（1.4 mM）和苯甲酸盐（3.6 mM）。这些数据表明，丙磺舒和水杨酸在脑中的分布受限可能归因于从脑ISF的有效流出，这可能是由BBB的MCT系统调节的。少

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