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 work investigates the effects of Pluronic block copolymers on the functional activity of MRP. METHODS: The studies examined the accumulation and efflux of the MRP selective probe fluorescein (FLU) in Panc-1 cell monolayers with and without Pluronic P85 ( P85), Pluronic L81 (L81) and Pluronic F108 (F108). RESULTS: Treatment of Panc-1 cells with P85 resulted in concentration-dependent increases in FLU accumulation and elimination of FLU sequestration in vesicular compartments in these cells. The effects of P85 were selective for FLU in the Panc-1 cell monolayers. Inhibition of MRP-mediated transport was dependent on the composition of Pluronic block copolymer: the more hydrophobic 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 similarities in the effects of Pluronic block copolymers on MRP and P-glycoprotein drug efflux systems suggest that a single unifying mechanism may explain the inhibition observed.[1]References
- Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers. Miller, D.W., Batrakova, E.V., Kabanov, A.V. Pharm. Res. (1999) [Pubmed]
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