Pluronic P85 enhances the delivery of digoxin to the brain: In vitro and in vivo studies

Drug delivery across the blood-brain barrier is limited by several mechanis ms. One important mechanism is drug efflux, mediated by several transport p roteins, 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 met hods. The hypothesis was that specific Pluronic copolymer systems enhance d rug delivery to the central nervous system through the inhibition of P-glyc oprotein. The effect of P85 on the cellular accumulation and transport of d igoxin, a model P-glycoprotein substrate, was examined in porcine kidney ep ithelial cells (LLC-PK1) transfected with the human MDR1 gene. The effect o f 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-transfect ed cells. Similar effects were observed for a prototypical P-glycoprotein s ubstrate rhodamine-123. P85 treatment decreased the basolateral-to-apical a nd increased the apical-to-basolateral digoxin flux across LLC-PK1-MDR1 cel l monolayers, and analogous results were observed with the in vitro BBB mon olayers. The coadministration of 1% P85 with radiolabeled digoxin in wild-t ype 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 c an enhance the delivery of digoxin to the brain through the inhibition of t he P-glycoprotein-mediated efflux mechanism.