Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or without Concomitant Use of P-Glycoprotein Inhibitors

Shicheng Yang, R. Neslihan Gursoy, Gregory Lambert, Simon Benita*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Purpose. 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 μM) 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.

Original languageEnglish
Pages (from-to)261-270
Number of pages10
JournalPharmaceutical Research
Volume21
Issue number2
DOIs
StatePublished - Feb 2004

Keywords

  • Microemulsion
  • P-glycoprotein inhibitors
  • Paclitaxel
  • Pharmacokinetics
  • Self-microemulsifying drug delivery system (SMEDDS)

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