Batrakova E V, Miller D W, Li S, Alakhov V Y, Kabanov A V, Elmquist W F
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
J Pharmacol Exp Ther. 2001 Feb;296(2):551-7.
Drug delivery across the blood-brain barrier is limited by several mechanisms. One important mechanism is drug efflux, mediated by several transport proteins, including P-glycoprotein. The goal of this work was to examine the effect of a novel drug delivery system, Pluronic block copolymer P85, on P-glycoprotein-mediated efflux from the brain using in vitro and in vivo methods. The hypothesis was that specific Pluronic copolymer systems enhance drug delivery to the central nervous system through the inhibition of P-glycoprotein. The effect of P85 on the cellular accumulation and transport of digoxin, a model P-glycoprotein substrate, was examined in porcine kidney epithelial cells (LLC-PK1) transfected with the human MDR1 gene. The effect of P85 on the directional flux across an in vitro BBB was also characterized. In vivo brain distribution studies were accomplished using wild-type and P-glycoprotein knockout mice. Pluronic increased the cellular accumulation of digoxin 3-fold in LLC-PK1 cells and 5-fold in the LLC-PK1-MDR1-transfected cells. Similar effects were observed for a prototypical P-glycoprotein substrate rhodamine-123. P85 treatment decreased the basolateral-to-apical and increased the apical-to-basolateral digoxin flux across LLC-PK1-MDR1 cell monolayers, and analogous results were observed with the in vitro BBB monolayers. The coadministration of 1% P85 with radiolabeled digoxin in wild-type mice increased the brain penetration of digoxin 3-fold and the digoxin level in the P85-treated wild-type mice was similar to that observed in the P-glycoprotein-deficient animals. These data indicate that Pluronic P85 can enhance the delivery of digoxin to the brain through the inhibition of the P-glycoprotein-mediated efflux mechanism.
药物透过血脑屏障的过程受到多种机制的限制。其中一个重要机制是药物外排，这一过程由包括P-糖蛋白在内的多种转运蛋白介导。本研究的目的是采用体外和体内方法，研究一种新型药物递送系统——普朗尼克嵌段共聚物P85对P-糖蛋白介导的药物从脑内流出的影响。研究假设是特定的普朗尼克共聚物系统通过抑制P-糖蛋白来增强药物向中枢神经系统的递送。在转染了人MDR1基因的猪肾上皮细胞（LLC-PK1）中，研究了P85对地高辛（一种典型的P-糖蛋白底物）的细胞摄取和转运的影响。还对P85在体外血脑屏障上的定向通量影响进行了表征。使用野生型和P-糖蛋白基因敲除小鼠完成了体内脑分布研究。普朗尼克使LLC-PK1细胞中的地高辛细胞摄取增加了3倍，在转染了LLC-PK1-MDR1的细胞中增加了5倍。对于典型的P-糖蛋白底物罗丹明-123也观察到了类似的效果。P85处理降低了地高辛通过LLC-PK1-MDR1细胞单层从基底外侧到顶端的通量，并增加了从顶端到基底外侧的通量，体外血脑屏障单层也观察到了类似结果。在野生型小鼠中，1%的P85与放射性标记的地高辛共同给药使地高辛的脑渗透率提高了3倍，P85处理的野生型小鼠中的地高辛水平与在P-糖蛋白缺陷动物中观察到的水平相似。这些数据表明，普朗尼克P85可以通过抑制P-糖蛋白介导的外排机制来增强地高辛向脑内的递送。
