Abstract
In the present study, we investigated the effect of large neutral amino acid modification in overcoming P-gp mediated cellular efflux of quinidine. L-isoleucine ester prodrug of quinidine (Ile-quinidine) was synthesized in our laboratory. [14C]-erythromycin was selected as a model substrate to study interaction of quinidine and Ile-quinidine with P-gp. Transport studies were conducted to study translocation kinetics of quinidine and Ile-quinidine in MDCK-MDR1 cells. In cellular accumulation study, uptake rate of [14C]-erythromycin elevated drastically in presence of cyclosporine A and GF 120918. This result indicates that [14C]-erythromycin is an excellent substrate of P-gp. Similarly, uptake rate of [14C]-erythromycin was enhanced significantly in presence of quinidine (25 and 50 μM). However, [14C]-erythromycin uptake rate remained fairly constant in presence of Ile-quinidine (25 μM). Apparent A-B and B-A permeability of quinidine observed in MDCK-MDR1 cells were 1.6 ± 0.2 × 10(-6) and 7.0 ± 0.4 × 10(-6)cm/s, a 4.4-fold difference. Moreover, A-B permeability of quinidine increased dramatically in the presence of cyclosporine A and GF 120918. Apparent permeability values of Ile-quinidine observed from A-B and B-A direction were 4.3 ± 0.9 × 10(-6) and 5.5 ± 0.4 × 10(-6)cm/s, a 1.3-fold difference. Importantly, A-B transport of Ile-quinidine did not change dramatically in the presence of cyclosporine and GF 120918. Based on these results, it was apparent that quinidine displayed higher substrate affinity toward P-gp relative to Ile-quinidine. Chemical or enzymatic hydrolysis of Ile-quinidine resulted in regeneration of low quantities of quinidine during transport studies. Competitive inhibition studies demonstrated that Ile-quinidine was recognized by multiple amino acid transporters such as LAT1, LAT2 and cationic amino acid transporter. In conclusion, chemical modification of quinidine with neutral amino acids results in circumvention of P-gp mediated drug efflux. Hence, amino acid transporter targeted prodrug delivery seems to be a viable strategy for improving drug accumulation in P-gp overexpressing cells.
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