Circumventing P-glycoprotein-mediated cellular efflux of quinidine by prodrug derivatization.

The objective of this study is to investigate whether transporter-targeted prodrug derivatization of quinidine, a model P-glycoprotein (P-gp) substrate, can circumvent P-gp-mediated efflux. The L-valine ester of quinidine (val-quinidine) was synthesized in our laboratory. Uptake and transport studies were carried out using the MDCKII-MDRI cell line at 37 degrees C for 10 min and 3 h, respectively. [3H]Ritonavir and cyclosporine were also used as model P-gp substrates to delineate the kinetics of translocation of val-quinidine across the MDCKII-MDRI cell monolayer. The rate of uptake of [3H]ritonavir by MDCKII-MDRI cells exhibited a 2-fold increase in the presence of 75 microM quinidine, but 75 microM val-quinidine did not demonstrate any effect on [3H]ritonavir uptake. The rate of transport of quinidine from the basolateral to the apical membrane [(18.3 +/- 1.25) x 10(-6) cm s(-1)] and from the apical to the basolateral membrane [(6.5 +/- 0.66) x 10(-6) cm s(-1)] exhibited a 3-fold difference. However, transport of val-quinidine from the apical to the basolateral membrane [(5.13 +/- 0.49) x 10(-6) cm s(-1)] and from the basolateral to the apical membrane [(6.17 +/- 1.28) x 10(-6) cm s(-1)] did not demonstrate any statistically significant difference. Moreover, cyclosporine, a potent P-gp substrate and/or inhibitor, did not alter the transport kinetics of val-quinidine. The rates of uptake of [3H]Gly-Sar and various amino acid model substrates were reduced in the presence of 200 microM val-quinidine. Results from this study clearly indicate that prodrug derivatization of quinidine into val-quinidine can overcome P-gp-mediated efflux. Val-quinidine once bound to a peptide or amino acid transporter is probably not recognized and cannot be accessed by the P-gp efflux pump. Transporter-targeted prodrug derivatization seems to be a viable strategy for overcoming P-gp-mediated efflux.