title: The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients.
abstract: OBJECTIVE
  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) × 10-6and (14.63 ± 3.11) × 10-6cm/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) × 10-6cm/s, p < 0.05] and lowered the S → M [Papp from (14.63 ± 3.11) to (13.35 ± 2.01) × 10-6cm/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Buraydah Private Colleges, P.O. Box 31717, Al-Qassim, 11451, Saudi Arabia. nzansar@gmail.com.|Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India. nzansar@gmail.com.
authors.forename: Naseem
authors.initials: N
authors.lastname: Akhtar
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
authors.forename: Abdul
authors.initials: A
authors.lastname: Ahad
authors.affiliation: Department of Clinical Pharmacy, Buraydah Private Colleges, P.O. Box 31717, Al-Qassim, 51418, Saudi Arabia.
authors.forename: Mohd Faiyaz
authors.initials: MF
authors.lastname: Khan
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Buraydah Private Colleges, P.O. Box 31717, Al-Qassim, 11451, Saudi Arabia.
authors.forename: Ayman
authors.initials: A
authors.lastname: Allaham
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi, 110062, India.
authors.forename: Sushama
authors.initials: S
authors.lastname: Talegaonkar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D005047:Etoposide; D014700:Verapamil