European journal of drug metabolism and pharmacokinetics · 2017
The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients.
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Akhtar Naseem, Ahad Abdul, Khan Mohd Faiyaz, Allaham Ayman, Talegaonkar Sushama
Аннотация
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) × 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.
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.
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) × 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.
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.