Naseem Akhtar, Abdul Ahad, Mohd Faiyaz Khan, Ayman Allaham, Sushama Talegaonkar
European journal of drug metabolism and pharmacokinetics 2016 Mar 25The 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. 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. 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) × 10(-6) and (14.63 ± 3.11) × 10(-6) cm/s, respectively, with a net efflux of 4.08. Addition of verapamil (200 µM), a P-glycoprotein inhibitor, elevated the transport from M → S [Papp from (3.58 ± 0.32) to (9.66 ± 1.55) × 10(-6) cm/s, p < 0.05] and lowered the S → M [Papp from (14.63 ± 3.11) to (13.35 ± 2.01) × 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. 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.
Naseem Akhtar, Abdul Ahad, Mohd Faiyaz Khan, Ayman Allaham, Sushama Talegaonkar. The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients. European journal of drug metabolism and pharmacokinetics. 2016 Mar 25
PMID: 27016067
View Full Text