Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies.
Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies.
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发表时间：
2001-02
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通讯作者：
E. Batrakova;Donald W. Miller;Shu Li;V. Alakhov;A. Kabanov;W. Elmquist
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作者：
E. Batrakova;Donald W. Miller;Shu Li;V. Alakhov;A. Kabanov;W. Elmquist
药物通过血脑屏障的传递受到几种机制的限制。一个重要的机制是药物外排，由几种转运蛋白介导，包括P-糖蛋白。这项工作的目的是研究一种新的药物输送系统，普朗尼克嵌段共聚物P85，对P-糖蛋白介导的流出从大脑使用在体外和体内的方法的效果。假设特定的Pluronic共聚物系统通过抑制P-糖蛋白增强药物向中枢神经系统的递送。在转染人MDR 1基因的猪肾上皮细胞（LLC-PK 1）中检测P85对地高辛（一种模型P-糖蛋白底物）细胞蓄积和转运的影响。还表征了P85对穿过体外BBB的定向通量的影响。使用野生型和P-糖蛋白敲除小鼠完成体内脑分布研究。Pluronic使LLC-PK 1细胞中地高辛的细胞蓄积增加3倍，使LLC-PK 1-MDR 1转染细胞中地高辛的细胞蓄积增加5倍。对于原型P-糖蛋白底物罗丹明-123也观察到类似的效果。P85处理降低了LLC-PK 1-MDR 1细胞单层的基底外侧至顶端的地高辛通量，并增加了顶端至基底外侧的地高辛通量，在体外BBB单层中观察到了类似的结果。在野生型小鼠中同时给予1%P85和放射性标记的地高辛可使地高辛的脑渗透增加3倍，并且在P85处理的野生型小鼠中地高辛水平与在P-糖蛋白缺陷动物中观察到的相似。这些数据表明，Pluronic P85可通过抑制P-糖蛋白介导的外排机制增强地高辛向脑的递送。
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.