Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers.
OBJECTIVE
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.
Miller
D W
DW
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6025, USA.
Batrakova
E V
EV
Kabanov
A V
AV
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019793:Fluorescein / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020442:Poloxamer / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D019793:Fluorescein; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020442:Poloxamer; D011108:Polymers; D013501:Surface-Active Agents