Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: I. Acute toxicity and pharmacokinetics studies

Abstract

Purpose: The aim of the present study was to evaluate the acute toxicity and pharmacokinetics of paclitaxel nanosuspensions stabilized with TPGS in mice.

Method: The paclitaxel nanosuspensions were prepared by evaporative precipitation into aqueous solution (EPAS) method, and freeze-dried powders of the nanosuspensions were obtained through lyophilization process. The morphology and particle size of nanosuspensions were determined by transmission electron microscope and Zetasizer, respectively. The acute toxicity and pharmacokinetics of paclitaxel nanosuspensions after intravenous administration to Kunming mice were studied. A marketed paclitaxel injectable solution was studied parallelly.

Results: The paclitaxel nanoparticles were in rod shape under transmission electron microscope, and their mean particle size was 135.4 ± 5.7 nm. Results of acute toxicity showed the LD50 of paclitaxel nanosuspensions was 98.63 mg/kg, twice more than that of the marketed injection (41.46 mg/kg). After intravenous injection paclitaxel nanosuspensions displayed different pharmacokinetic properties in comparison with the marketed injectable solution, including a decreased initial drug concentration, increased plasma half-life, AUC and MRT.

Conclusions: The paclitaxel nanosuspensions prepared in this study could markedly enhance the tolerance dosage in mice, and manifest different pharmacokinetic properties compared with the solution.

Keywords: Acute toxicity; Colloidal drug delivery system; Nanosuspensions; Paclitaxel; Pharmacokinetics.