论文部分内容阅读
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 (PK), excretion and tissue distribution of glufosfamide in experimental animals. Methods: The Beagle dogs were administrated iv at dose of 60, 30, and 15 mg.kg-1, the plasma concentrations were determined by LC-MS / MS, and the pharmacokinetic parameters were calculated by 3P97 software. Eighteen mice were divided into three groups, the tail iv given 300 mg.kg-1 glufosinate, decapitation sacrifice, determination of glufosfamide tissue distribution. Ten rats were divided into two groups and given 300 and 100 mg.kg-1 glufosfamide respectively. Urine and fecal samples were collected at different time points after administration to evaluate the excretion of glufosfamide. Results: Glufosamide showed a two-compartment model in Beagle dogs. The T1 / 2β and AUC of 60, 30 and 15 mg · kg-1 groups were 614.8, 544.0 and 596.3 min and 37173.1, 2176.0 and 10741.7 μg, respectively. mL-1.min. After 4 h of administration, the concentration of the drug in the kidney was the highest (2780.2 μg.g-1), and it was also higher in the ovary and uterus (2684.5 and 2369.4 μg.g-1, respectively). After 300mg.kg-1 glufosfamide was injected into the tail vein of rats, the urinary excretion of the prototype drug was 26.9% and the excretion rate peaked at 5-8 h (1.36 mg.h-1); the excretion of manure was 0.12 %, Excretion rate peaked at 2 ~ 5 h, 4.3μg.h-1; when the dose was 100 mg.kg-1, the urinary excretion rate of the prototype drug was 46.8%, and the excretion rate peaked at 8 ~ 12 h , Which was 1.29 mg · h-1. The manure excretion was 0.21% and the excretion rate of excrement reached the peak value of 6.1μg.h-1 at 5-8 h. CONCLUSION: The plasma concentration of glufosfamide after intravenous administration has a linear relationship with the dose of AUC, and is widely distributed in various tissues of mice with more distribution of kidney, ovary, uterus, lung and spleen. Within 1-2 h % ~ 50% of the prototype drug excreted from the urine.