Abstract
Background and objectives The selection of suitable functional excipients with low toxicity index and having P-glycoprotein inhibitory characteristics represents a major innovative step in designing a promising formulation for oral chemotherapy. This study was aimed at investigating the chemosensitizing effect of selected pharmaceutical excipients to improve the in vivo pharmacokinetic performance of VP-16.
Methods The pharmaceutical excipients having P-glycoprotein inhibitory activity were screened by shake flask method for their VP-16 solubilization capacity. The cumulative amount of VP-16 was determined with or without the selected pharmaceutical excipients at three different concentrations (0.1 % w/v, 0.5 % w/v and 1 % w/v) by an everted gut sac technique. Moreover, pharmacokinetic studies were also performed to determine the oral bioavailability assessment of VP-16 in albino male Wistar rats.
Results The absorptive transport from mucosal-to-serosal (M -> S) and secretory transport from serosal-to-mucosal (S -> M) for VP-16 solution over 90 min were found to be (3.58 +/- 0.32) x 10(-6) and (14.63 +/- 3.11) x 10-6 cm/s, respectively, with a net efflux of 4.08. Addition of verapamil (200 mu M), a P-glycoprotein inhibitor, elevated the transport from M -> S [Papp from (3.58 +/- 0.32) to (9.66 +/- 1.55) x 10(-6) cm/s, p < 0.05] and lowered the S -> M [Papp from (14.63 +/- 3.11) to (13.35 +/- 2.01) x 10-6 cm/s, p < 0.01], with a net efflux of 1.38. The relative bioavailability of VP-16 following oral administration (4.5 mg/kg) in rats was increased significantly (p < 0.01) in presence of Labrasol micellar solution at a concentration of 5 % (w/v) when compared with VP-16 solution alone.
Conclusion The findings suggest that pharmaceutical excipients may be employed in the development of drug delivery systems to improve the oral bioavailability of drugs having low solubility and/or less permeability as a result of substantial P-glycoprotein mediated efflux.