替加氟磁性长循环热敏脂质体大鼠体内的药代动力学评价

背景：在脂质体内加入纳米磁性粒子，可增强脂质体的靶向性；同时采用交变磁场进行局部加热，可以增强药物释放的可控性以及疗效。 目的：评价替加氟磁性长循环热敏脂质体的药代动力学规律和靶向性。 设计、时间及地点：随机对照，动物体内实验，于2007-06/12在中南大学国家卫生部肝胆肠外科研究中心实验室完成。 材料：反相蒸发超声法制备替加氟磁性长循环热敏脂质体和替加氟长循环脂质体。 方法：正常Wistar大鼠72只随机分为3组，每组24只，前2组经肝动脉分别灌注游离替加氟注射液或替加氟长循环脂质体，另一组经肝动脉灌注替加氟磁性长循环热敏脂质体，同时进行磁控并加热。 主要观察指标：采用高效液相色谱仪检测生物组织样品中替加氟的浓度，采用药动学软件3p97求得其药动学参数及各组织药物浓度-时间曲线下面积。 结果：磁控并加热的替加氟磁性长循环热敏脂质体组的肝内8 h药时曲线下面积是游离药物组的17.45倍，是替加氟长循环脂质体组的3.9倍，其肝外组织血浆、肾器官中比游离组低；其肝靶向效率达到73.9%。替加氟长循环脂质体组半衰期比替加氟游离药物组明显延长。 结论：替加氟磁性长循环热敏脂质体显著增加药物在肝脏的分布，从而可能间接降低药物的肾毒性。

Pharmacokinetics research on Tegafur long-circulating thermosensitive magnetoliposomes in rats

BACKGROUND: Magnetoliposomes show the well loading drug, magnetic targeting and biocompatibility controllability by means of alternating magnetic field. OBJECTIVE: To study the targeting and pharmacokinetics regularity of Tegafur long-circulating thermosensitive magnetoliposome. DESIGN, TIME AND SETTING: The experiment, a randomized controlled study, was carried out in Laboratory of National Hepatobiliary & Enteric Surgery Research Center, Central South University from June to December 2007. MATERIALS: Tegafur long-circulating thermosensitive magnetoliposome and Tegafur long-circulating magnetoliposome were prepared using reversed-phase evaporation and ultrasound method. METHODS: A total of 72 healthy conventional Wistar rats were divided into three groups at random, each group contained 24 animals. Rats were processed into hepatic arterial administration of free Tegafur solution, Tegafur long-circulating liposome or Tegafur long-circulating thermosensitive magnetoliposome following magnetic controlling and heating. MAIN OUTCOME MEASURES: The Tegafur concentrations in biological tissues were detected with high performance liquid chromatograph. Pharmacokinetical parameters were determined using 3p97 software. Area under the plasma concentration-time curve was also calculated. RESULTS: Area under the plasma concentration-time curve of 8 hours at liver in Tegafur long-circulating thermosensitive magnetoliposome group was 17.4 times of that of free drug group, and 3.9 times of that of Tegafur long-circulating liposome group. Its concentrations in serum and kidney were lower than those in free drug group. Its liver-targeted ratio was 73.9%. T1/2 (half-life) was longer in Tegafur long-circulating liposome group than free drug group. CONCLUSION: Tegafur long-circulating thermosensitive magnetoliposome can increase markedly the drug contribution in liver and thus decrease nephrotoxicity.