葡膦酰胺在实验动物体内的药代动力学、组织分布及排泄

Pharmacokinetics,tissue distribution and excretion of glufosfamide in animals

目的:研究葡膦酰胺在实验动物体内的药代动力学(PK)、排泄及组织分布特征。方法:Beagle犬iv给药,剂量为60,30,15 mg.kg-1,LC-MS/MS测定血药浓度,3P97软件计算药代动力学参数。18只小鼠分为3组,尾iv给予300 mg.kg-1葡膦酰胺,断头处死,测定葡膦酰胺组织分布。10只大鼠分为2组,分别给予300和100 mg.kg-1葡膦酰胺,给药后收集不同时间段的尿和粪样品,评价葡膦酰胺的排泄过程。结果:葡膦酰胺在Beagle犬体内代谢分布呈二室模型,60,30,15 mg.kg-1各组T1/2β和AUC值分别为614.8,544.0,596.3 min和37173.1,21760.0,10741.7μg.mL-1.min。小鼠给药4 h后,在肾脏中的药物浓度最高(2780.2μg.g-1);在卵巢和子宫中分布亦较高,分别为2684.5和2369.4μg.g-1。大鼠尾静脉注射300 mg.kg-1葡膦酰胺后,原型药物经尿排泄量为26.9%,排泄速率在5～8 h达到峰值,为1.36 mg.h-1;经粪排泄量为0.12%,排泄速率在2～5 h达到峰值,为4.3μg.h-1;剂量为100 mg.kg-1时,原型药物经尿排泄量为46.8%,排泄速率在8～12 h后达峰值,为1.29 mg.h-1;经粪排泄量为0.21%,经粪排泄速率在5～8 h达峰值,为6.1μg.h-1。结论:葡膦酰胺静脉给药后血药浓度、AUC与给药剂量呈线性关系;在小鼠各组织分布广泛,以肾、卵巢、子宫、肺、脾分布较多;1～24 h内25%～50%以原型药物从尿排出。

Objective： To study the pharmacokinetics, distribution and excretion of glufosfmide in animals. Methods： 6 beagle dogs were given 60, 30, 15 mg·kg^-1 glufosfmide individually by iv. Plasma concentration was analyzed by LC-MS/MS. Pharmacokinetic parameters were calculated by 3P97 software. 18 mouse were divided into 3 groups and given 300 mg·kg^-1 glufosfmide by iv, and thereafter decapitated to determine the tissues distribution. 10 rats were divided into 2 groups and given 100 mg·kg^-1 300 mg·kg^-1 glufosfmide individually. Samples of urine and feces were collected and determined for the excretion study. Results： The pharmacokinetics of glufosfamide in beagles was consistent with the two-compartment model. T1/2β and AUC of 60,30,15 mg·kg^-1 group were 614.8,544.0,596.3 min and 37173.1, 21760.0, 10741.7 （μg·mL^-1）· min. The maximum concentration appeared in the kidney（2780.2μg·g^-1）, ovary （2684.5μg·g^-1） and （uterus） of mouse 4 h after injection. For 300 mg·kg^-1 glufosfamide in rats, 26.9% prototype was excreted through urine, with a maximum excretion rate of 1.36 mg·h^-1 5-8 h after injection; 0.12% was excreted through feces, with a maximum excretion rate of 4.3μg·h^-1 2-5 h after injection. For 100 mg·kg^-1 glufosfamide in rats, 46.8 % was excreted through urine, with a maximum excretion rate of 1.29 mg·h^-1 8-12 h after injection; 0.21% was excreted through feces, with a maximum excretion rate of 6.1μg·h^-1 5-8 h after injection. Conclusions： After intravenous injection of glufosfamide, plasma concentration, AUC demonstrate linear relationship with the dose. The drug is widely distributed in mouse, mainly in kidney, ovary, uterus, lung, spleen. 25%-50 % prototype is excreted through the urine within 1-24 h.