In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates

Recently, several polymers have been reported to modulate drug absorption by inhibition of intestinal efflux pumps such as multidrug resistance proteins (MRPs) and P-glycoprotein (P-gp). The aim of the present study was to evaluate the efficiency of thiolated poly(acrylic acid) (PAA-Cys) to act as a drug absorption modulator for MRP2 efflux pump substrates in vivo, using sulforhodamine 101 as representative MRP2 substrate. In vitro, the permeation-enhancing effect of unmodified PAA and PAA250-Cys, displaying 580 μmol free thiol groups per gram polymer, was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to that of the buffer control, the sulforhodamine 101 transport in the presence of 0.5% unmodified PAA250 and 0.5% (w/v) PAA250-Cys was 1.3- and 4.0-fold improved, respectively. In vivo, sulforhodamine 101 solutions containing 4% (w/v) unmodified PAA250 or 4% (w/v) thiolated PAA250 were orally given to rats. The PAA250-Cys solution increased the area under the plasma concentration-time curve (AUC0-12) of sulforhodamine 101 3.8-fold in comparison to control and 2.2-fold in comparison to unmodified PAA250. This in vivo study revealed that PAA250-Cys significantly increased the oral bioavailability of MRP2 substrate sulforhodamine 101.