Enhanced Oral Bioavailability and Absorption Mechanism Study of N3-0-Toluyl-Fluorouracil-Loaded Liposomes

摘要

The present investigation attempts to increase oral absorption of N3-O-Toluyl-Fluorouracil (TFu), one of the new and effective 5-fluorouracil prodrugs, by employing liposomal techniques TFu-loaded liposomes with different sizes all resulted in higher bioavailabilities than TFu aqueous suspensions after oral administration, and the gastrointestinal absorption increased with the reduction of lipo-some sizes In order to investigate the enhancing absorption mechanism of TFu-loaded liposomes, the everted gut sac experiments were applied to examine the influences of different factors. It was found that the uptake increased linearly with the concentration of TFu while the intestinal permeability coefficients changed slightly and the absorption process fitted with the Fick's diffusion law in the range of 5~20 /xg mL~1. The oral absorption of TFu-loaded liposomes might be a non-carrier-mediated and energy-independent, passive transport way. The liposomal bilayer was not stable enough and proned to be degraded partly in gastrointestinal tract (drug entrapment efficiency reduced by 5%~17%). The comparative studies between TFu-loaded liposomes and TFu solid lipid dispersions indicated that the two formulations had the same effects on enhancing the oral absorption of TFu. It could be concluded that it was the free drug but not the intact liposomes that penetrated the intestinal wall; the increased affinity between TFu-loaded liposomes and the gut liquid caused better dispersion of TFu in the gastrointestinal tract, prolonged the drug residence time in the absorption sites and resulted in better absorption effects. The decreasing liposomes sizes resulted in an increase in surface area, saturation solubility and consequently, and an increase in the bio-adhesion to the gastrointestinal tract wall thus increasing the oral bioavailability.