Evidence for modulation of P-glycoprotein-mediated efflux by methoxypolyethylene glycol-block-Polycaprolactone amphiphilic diblock copolymers.
OBJECTIVE
The purpose of this study was to investigate the pathways involved in rhodamine 123 (R-123) accumulation enhancement in Caco-2 cells with a low molecular-weight methoxypolyethylene glycol-block-polycaprolactone (MePEG-b-PCL) diblock copolymer.


METHODS
R-123 accumulation by Caco-2 cells with MePEG17-b-PCL5 was measured in the presence of endocytosis inhibitors or under ATP depletion conditions. Directional flux studies were conducted with cell monolayers on Transwell plates.


RESULTS
Endocytosis inhibitors had no effect on reducing R-123 accumulation with MePEG17-b-PCL5. The apical to basolateral (AP-->BL) flux of R-123 with MePEG17-b-PCL5 or verapamil was similar to R-123 alone. However the BL-->AP flux was significantly decreased with MePEG17-b-PCL5 and verapamil. The efflux ratio for R-123 flux was 3.2 and was reduced to 1.06 with MePEG17-b-PCL5 confirming the inhibition of P-glycoprotein (P-gp)-mediated efflux. R-123 accumulation at the conclusion of each of the flux experiments was similar for MePEG17-b-PCL5 and verapamil in the BL-->AP direction. The AP-->BL direction demonstrated a 2-fold increase for verapamil and a 5-fold increase with MePEG17-b-PCL5. This difference in R-123 accumulation was possibly due to the diblock enhancing passive membrane diffusion of R-123.


CONCLUSIONS
MePEG17-b-PCL5 diblock reduced R-123 efflux through inhibition of P-gp efflux, and unimers may interact with cell membranes, increasing permeability and enhancing R-123 influx through increased transmembrane diffusion.
Zastre
Jason
J
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Jackson
John
J
Burt
Helen
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001692:Biological Transport; D018938:Caco-2 Cells; D004337:Drug Carriers; D004705:Endocytosis / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D007546:Isoquinolines; D018613:Microscopy, Confocal; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers / Q000138:chemical synthesis / Q000494:pharmacology*; D020112:Rhodamine 123; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D005456:Fluorescent Dyes; D007546:Isoquinolines; D011091:Polyesters; D011108:Polymers; D020112:Rhodamine 123; C016240:polycaprolactone; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; C017475:lucifer yellow; D014700:Verapamil