摘要
目的:观察新型FXa抑制剂知非沙班采用不同溶剂口服给药对犬PK-PD的影响。方法:在离体酶活性实验中,采用生色底物法测定不同浓度的知非沙班对FXa的抑制活性,计算IC50值;在动物实验中,知非沙班分别采用0.5%的CMC-Na制备成混悬液和采用含PEG400、乙醇、水(体积比3∶1∶1)的混合溶剂制备成溶液,对犬以1 mg·kg^(-1)的剂量灌胃给药,分别在给药前、给药后0.5、1、2、3、4、6、9、12、15、24 h股静脉采血,分离血浆后,LC-MS/MS测定各个时间点血药浓度和药代动力学参数,生色底物法测定各时间点的FXa活性。结果:离体酶活性检测结果显示,知非沙班的IC50值11.1 nmol·L^(-1),表明其有良好的FXa抑制活性;动物实验结果显示,以CMC-Na为溶剂,知非沙班吸收缓慢,血药浓度低,FXa抑制活性低;以混合溶液为溶剂,知非沙班吸收迅速,血药浓度显著升高,FXa抑制活性明显增强。结论:新型口服FXa抑制剂知非沙班使用CMC-Na和混合溶剂作为溶剂,对犬口服后的药物吸收和药效学发挥有显著的影响。
Objective： To study the effects of oral administration using different solvents of novel FXa Inhibitor Zifaxaban on PK-PD in dogs. Methods： In the experiment of enzyme assays in vitro,the inhibitory activity of different concentrations of Zifaxaban on FXa was determined by the chromogenic substrate method,and the IC50 value was calculated. In animal experiments,Zifaxaban was prepared into a suspension by 0. 5% CMC-Na and solution by mixed solvent with PEG400,ethanol and water（ 3∶ 1∶ 1） respectively. The dogs were then administered orally at a dose of 1 mg·kg^（-1）. Blood samples were collected from femoral vein before administration and at 0. 5,1,2,3,4,6,9,12,15 and 24 h after administration. After separation of plasma,LC-MS/MS was used to determine plasma concentration and pharmacokinetic parameters at each time point. The chromogenic substrate method was used to determine the FXa activity at each time point. Results： The isolated enzyme assays showed that the IC50 value of Zifaxaban was 11. 1 nmol·L^（-1）,which indicated that it had a good FXa inhibitory activity. The results of animal experiments showed that Zifaxaban absorbed slowly with CMC-Na as solvent,had low blood concentration and low FXa inhibitory activity. With mixed solvent as solvent,Zifaxaban absorbed rapidly,and blood concentration was significantly increased,while FXa inhibitory activity was significantly enhanced. Conclusion： The new oral FXa inhibitor Zifaxaban using CMC-Na and mixed solvent as solvents had a significant impact on drugs absorption and pharmacodynamics of dogs after oral administration.
作者
邱小妙
张珊
石冰卓
王维亭
赵专友
孙双勇
QIU Xiao-miao;ZHANG Shan;SHI Bing-zhuo;WANG Wei-ting;ZHAO Zhuan-you;SUN Shuang-yong(Tianjin Medical University,Tianjin 300070,China;Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co.Ltd,Tianjin 300193,China)
出处
《中国药物评价》
2018年第3期172-177,共6页
Chinese Journal of Drug Evaluation
基金
天津市应用基础与前沿技术研究计划青年项目(No 14JCQNJC13300)
天津市特支计划青年拔尖人才基金(TJTZJH-QNBJRC-2-7)
