title: Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug delivery system with or without concomitant use of P-glycoprotein inhibitors.
abstract: OBJECTIVE
  The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors.
  
  
  METHODS
  Paclitaxel SMEDDS formulation was optimized, in terms of droplet size and lack of drug precipitation following aqueous dilution, using a ternary phase diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting microemulsions were evaluated. The plasma concentrations of paclitaxel were determined using a HPLC method following paclitaxel microemulsion administrations at various doses in rats.
  
  
  RESULTS
  Following 1:10 aqueous dilution of optimal paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4 nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various doses. There was a significant improvement in area under the curve (AUC) and time above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of Taxol following coadministration of both formulations with 40 mg cyclosporin A (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following coadministration of tacrolimus and etoposide, but plasma drug concentrations did not reach the therapeutic level. The nonlinear pharmacokinetic trend was not modified after paclitaxel was formulated in SMEDDS.
  
  
  CONCLUSIONS
  The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Yang
authors.forename: R Neslihan
authors.initials: RN
authors.lastname: Gursoy
authors.forename: Gregory
authors.initials: G
authors.lastname: Lambert
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004347:Drug Interactions; D004355:Drug Stability; D004655:Emulsions; D007275:Injections, Intravenous; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004655:Emulsions; D016572:Cyclosporine; D017239:Paclitaxel