5-氟尿嘧啶磁性脂质体纳米粒在大鼠体内药物动力学研究

Pharmacokinetics research on 5-Fluorouracil magnetic liposome nanoparticles (FMLNP) in rats

目的探讨5-氟尿嘧啶磁性脂质体纳米粒(FMLNP)在大鼠体内的药物动力学规律,求算药动学参数并进一步考察其靶向性。方法分别经肝动脉给以游离5-Fu、FMLNP肝区不加磁场及FMLNP肝区加磁场三种方式给药,于给药后6min、10min、0.5h、1h、2h、4h、6h、8h测血液及各组织的药物浓度,比较不同给药方式下各组织的药时分布曲线、AUC值(药时曲线下面积)直条图;根据血液的药时浓度,采用3P87药动学处理软件,对三种方法血浆中的药物浓度经时数据进行处理,确定最佳房室模型,求算药动学参数;根据血药浓度及“3P87”软件求得参数、分析结果,应用“MATLAB”软件进行房室仿真,从另一方面检验“3P87”软件拟合的可信度。结果与游离5-Fu组、FMLNP肝区不加磁场组比较,经肝动脉给以FMLNP并在肝区加磁场后,药物在肝内峰值浓度均明显升高(P<0.01),且滞留时间延长,肝外各组织药物浓度均低;经肝动脉给以游离5-Fu组、FMLNP肝区不加磁场组均为二室模型,而FMLNP肝区加磁场组符合三室模型。结论经肝动脉给以FMLNP并配合外加磁场,药物在肝区的靶向选择性最好,滞留时间延长,FMLNP改变了5-Fu在大鼠体内的分布特性,延长了5-Fu的半衰期,提高了5-Fu的生物利用度,具有很强的肝脏靶向性和缓释性。

[Objective] To explore the pharmacokinetics rule of FMLNP in rats and work out the pharmacokinetics parameter and observe its targeting function. [Methods] Three administration types were designed, including injecting free 5-Fu, FMLNP in the absence of magnetic field and in the presence of magnetic field via hepatic artery respectively. The serum and other tissues＇ medicine concentration was surveyed at 6 minutes, 10 minutes, 30 minute, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours after medicine was given. Medicine-time distribution curves and area under curve （AUC） bar charts of tissues with three administration types were compared. According to the medicine-time concentration of serum of each group, we found the optimization compartment model and worked out the phannacokinetics parameter after dealing with ＂3P87＂ phannacokinetics software, then simulated it with ＂MAT- LAB＂ soft ware in order to check the reliability of ＂3P87＂. [Results] Compared group A and B, the peak concentration of medicine increased in targeting site of group C （P 〈0.01）, persistence time prolonged but the peak concentration out of targeting site decreased. FMLNP with magnetic field in targeting site group accorded with three-compartment model but all other groups were two-compartment model. [Conclusion] Treatment with FMLNP via hepatic artery administration in the presence of magnetic force the liver targeting site showed significantly greater targeting and the medicine stayed longer than any other model. FMLNP changed the distribution characteristics of 5-Fu in mr, prolonged its half-life period and elevated its biological availability, which proved its good liver targeting function and slow-release.