Pharmacokinetic comparison of intravenous carbendazim and remote loaded carbendazim liposomes in nude mice.

摘要

Carbendazim is a novel anticancer agent. The aim of this study was to prepare and characterize a remote loaded liposome preparation of carbendazim, and compare its pharmacokinetic profile to that of unencapsulated carbendazim. Carbendazim was encapsulated in liposomes composed of sphingomyelin-cholesterol (3:1, w/w) by remote loading in response to a transmembrane pH gradient (pH 0.5 in/pH 4.0 out), which resulted in encapsulation of more than 95% of the available drug in preformed vesicles. High drug/lipid ratios were prepared which correspond to a molar ratio of up to 0.8. Physical isolation of the free drug and dialysis were used to determine the in vitro release of carbendazim from liposomes. The release was independent of the initial drug/lipid ratio and choice of internal buffer composition. Liposomal carbendazim (200 mg kg(-1)) was intravenously administered to athymic nude mice and the serum levels of free carbendazim were determined by HPLC analysis after a methanol-induced protein precipitation. Administration of liposomal carbendazim to mice resulted in significant alterations in the pharmacokinetics. Serum levels of free carbendazim were approximately 10-fold greater than those achieved for the same dose of unencapsulated drug. Liposomal carbendazim showed both high C(max), AUC and low clearance rate. Liposomal carbendazim and unencapsulated carbendazim displayed a similar terminal half-life (43-48 min). The relatively large volume of distribution of carbendazim suggests that the compound may partially enter cells or be bound to some extravascular structures. The results indicate that the liposomal formulation of carbendazim significantly increases its blood concentrations.