The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients
- 25 March 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Drug Metabolism and Pharmacokinetics
- Vol. 42 (2), 191-199
- https://doi.org/10.1007/s13318-016-0332-7
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) × 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.Keywords
Funding Information
- University Grants Commission
This publication has 27 references indexed in Scilit:
- The emerging role of P-glycoprotein inhibitors in drug delivery: a patent reviewExpert Opinion on Therapeutic Patents, 2011
- P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of EtoposideClinical Cancer Research, 2010
- Inhibiting efflux with novel non-ionic surfactants: Rational design based on vitamin E TPGSInternational Journal of Pharmaceutics, 2009
- Lipid excipients and delivery systems for pharmaceutical development: A regulatory perspectiveAdvanced Drug Delivery Reviews, 2008
- Dose translation from animal to human studies revisitedThe FASEB Journal, 2007
- Lipid Formulation Strategies for Enhancing Intestinal Transport and Absorption of P-Glycoprotein (P-gp) Substrate Drugs: In vitro/In vivo Case StudiesJournal of Pharmaceutical Sciences, 2007
- Polyethylene glycol–phosphatidylethanolamine conjugate (PEG–PE)-based mixed micelles: Some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated effluxInternational Journal of Pharmaceutics, 2006
- Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivoInternational Journal of Pharmaceutics, 2004
- Pharmacokinetic Optimisation of Treatment with Oral EtoposideClinical Pharmacokinetics, 2004
- Active secretion and enterocytic drug metabolism barriers to drug absorptionAdvanced Drug Delivery Reviews, 2001