Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers

Purpose. Using monolayers of human pancreatic adenocarcinoma cells (Panc-1) that express multidrug resistance-associated protein (MRP), the present wo rk investigates the effects of Pluronic block copolymers on the functional activity of MRP. Methods. The studies examined the accumulation and efflux of the MRP select ive probe fluorescein (FLU) in Panc-1 cell monolayers with and without Plur onic P85 (P85), Pluronic L81 (L81) and Pluronic F108 (F108). Results. Treatment of Panc-1 cells with P85 resulted in concentration-depen dent increases in FLU accumulation and elimination of FLU sequestration in vesicular compartments in these cells. The effects of P85 were selective fo r FLU in the Panc-1 cell monolayers. Inhibition of MRP-mediated transport w as dependent on the composition of Pluronic block copolymer: the more hydro phobic copolymer had the greater effect on FLU uptake in Panc-1 monolayers (L81 > P85 > F108). Conclusions. This paper demonstrates for the first time that Pluronic block copolymers inhibit multidrug resistance-associated protein (MRP). The simi larities in the effects of Pluronic block copolymers on MRP and P-glycoprot ein drug efflux systems suggest that a single unifying mechanism may explai n the inhibition observed.