Tegafur [1-(tetrahydro-2-furanyl)-5-fluorouracil](TF), a masked form of 5-fluorouracil (5-FU), is an effective antitumor agent. Oral administration of TF plus uracil (U) (14 mole/mole) (UFT) is more effective than that of TF alone. The relative bioavailability of UFT was studied in beagle dogs. A single oral administration of UFT test capsules or reference capsules containing 100 mg TF and 224 mg U was given to each dog according to a random crossover design. The drug concentrations in plasma were determined by high performance liquid chromatography (HPLC). The relative bioavailabilities of TF and 5-FU were ( 106.89± 21.74)% and ( 102.32± 24.02)%, respectively. The pharmacokinetic parameters, including C_ max, AUC_ 0~t and AUC_ 0~∞, show no significant difference (P 0.05). Statistical results show that the two preparations are bioequivalent ( P0.05).
The pharmacokinetics of huperzine A in dogs after single intravenous and oral administrations was investigated. Concentrations of huperzine A were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated by non-compartmental methods. After single intravenous administration, the Cmax, T1/2, AUC0-t, AUC0-∞, CL, Vd and Vss were 5.55 ± 1.61 μg/L, 5.02 ± 0.31 h, 16.04 ± 5.24, 16.49 ± 5.29 μg·h/L, 0.66 ± 0.19 L/h/kg, 4.76 ± 1.46, and 3.93 ± 1.54 L/kg, respectively. After single oral administration, the Cmax, Tmax, T1/2, AUC0-t, AUC0-∞ and oral bioavailability were 2.60 ± 0.60 μg/L, 1.25 ± 0.50 h, 5.71 ± 2.25 h, 12.90 ± 3.19, 13.78 ± 3.24 μg·h/L, and 94.4 ± 36.5 %, respectively. In conclusion, huperzine A had a rapid and nearly complete oral absorption and was extensively distributed into tissues after drug administration in dogs.
The present work provides a new, well characterized hydroxyl functionalized biocompatible and degradable polymer that could be suitable for many different biomedical applications. Poly(2-hydroxyethyl methacrylate) (PHEMA) is a widely used and researched biocompatible polymer, but lacks degradability. In this work, degradable and less toxic PHEMA with ester linkages in the backbone could be successfully made by radical copolymerization with cyclic ketene acetal. The protection–deprotection chemistry at the hydroxyl group of HEMA was necessary for the formation of targeted polymers. The structure of the resulting polymers was unambiguously proved by 2D NMR techniques. The polymers were significantly less toxic with cell viabilities of more than 80% even for very high polymer concentrations (100 mg mL−1). The polymers were hydrolytically degradable under basic conditions and also showed surface and bulk degradation using macrophages. We also demonstrated promising positive results for the use of such polymers as sustained drug delivery systems.
Huperzine A loaded poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared by an oil/water (o/w) solvent evaporation technique. With a decrease of the ratio of o/w from 1 : 100 to 1 : 50, the encapsulation efficiency was reduced about 4%. Increasing the PVA concentration from 0.5 to 2% reduced the percentage encapsulation efficiency of huperzine A from 60.7 to 47.4% and the particle size of microspheres from 84.2 to 26.2 μm. The addition of stearic acid improved the encapsulation efficiency, but also accelerated the in vitro release of hupezine A from microspheres. After i.m. administration of huperzine A loaded microspheres in mice, huperzine A was sustained released from the PLGA microspheres up to 12 d with a low initial burst. Passive avoidance test of mice showed that the microspheres formulation offered an improved therapeutic efficiency in the treatment of the impaired memory of the mice superior to injection gastric (i.g.) administration of huperzine A suspension at the same dose, whose therapeutic efficiency was similar as that of a 50% reduced dose of the microspheres formulation.
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