疏血通注射液对大鼠体内华法林抗凝作用的影响

赵海峰+孙佳慧+刘爽+刘艳+刘高峰

[摘要]研究疏血通注射液对大鼠体内华法林抗凝作用的药效学和药动学影响，为临床合理用药提供参考。进行单剂量华法林研究时，将Wistar大鼠随机分成空白对照组（A组）、疏血通注射液给药组（B组）、华法林对照组（C组）、疏血通注射液与华法林联合给药组（D组）；进行稳态华法林研究时，将Wistar大鼠随机分成华法林对照组（E组）、疏血通注射液与华法林联合给药组（F组）。用血凝分析仪测定凝血酶原时间（PT）和活化部分凝血活酶时间（APTT），并计算国际标准化比值（INR），进行疏血通注射液对单剂量和稳态华法林药效学影响的研究；用UPLC-MS/MS联合手性色谱柱技术测定r-华法林和s-华法林的血药浓度，并计算大鼠体内药代动力学参数，研究疏血通注射液对单剂量和稳态华法林的药动学影响。单剂量华法林实验结果显示，疏血通注射液本身可使大鼠的PT，INR显著升高（P<0.01），APTT升高（P<0.05）；与华法林联用后，与华法林对照组相比，PT，INR显著升高（P<0.01），APTT升高（P<0.05），s-华法林和r-华法林的药动学参数C_max，AUC0-t，AUC0-∞均升高，t1/2延长，CL/F降低。稳态华法林实验结果显示，与疏血通注射液联用后，华法林的PT，INR显著升高（P<0.01），s-华法林和r-华法林的血药浓度均升高。该研究结果表明，疏血通注射液本身具有抗凝血作用，与华法林联用可产生药效学协同作用；两药联用还可减慢华法林的代谢，产生药动学相互作用。疏血通注射液可明顯增强华法林的抗凝作用，提示临床用药时应尽量避免两药联合应用，以降低出血风险，如必须联用，应密切监测，以保障患者用药安全。

[关键词] 华法林； 疏血通注射液； 药物相互作用； 抗凝作用

[Abstract] To explore the effect of Shuxuetong injection on the pharmacodynamics and pharmacokinetics of warfarin in rats， and to provide reference for rational drug use. In studies on the single dose of warfarin， Wistar rats were randomly divided into four groups： blank control group（group A）， Shuxuetong injection group（group B）， warfarin control group（group C）， and warfarin+Shuxuetong injection group（group D）. In studies on the steady state of warfarin， Wistar rats were randomly divided into warfarin control group（group E） and warfarin+Shuxuetong injection group（group F）. To investigate the pharmacodynamic effect of Shuxuetong injection on warfarin， prothrombin time（PT） and activated partial thromboplastin time（APTT） were measured by coagulation analyzer， and international normalized ratio（INR） was calculated. To investigate the pharmacokinetic effect of Shuxuetong injection on warfarin， the blood concentrations of s-warfarin and r-warfarin were determined by UPLC-MS/MS combined with technology of chiral chromatographic column， and the related pharmacokinetic parameters were calculated accordingly. The results on the single dose of warfarin showed that Shuxuetong injection markedly increased PT， INR（P<0.01）， and APTT（P<0.05）. Meanwhile， when Shuxuetong injection was co-administrated with warfarin， it significantly increased PT， INR（P<0.01）， and APTT（P<0.05） as compared with warfarin control group. In addition， increased pharmacokinetic parameters including C_max， AUC0-t and AUC0-∞， prolonged t1/2， and decreased CL/F were observed for s-warfarin and r-warfarin. The results of the steady state of warfarin suggested that Shuxuetong injection significantly increased PT and INR of warfarin（P<0.01）， and elevated the plasma concentrations of s-warfarin and r-warfarin when co-administrated with warfarin. These findings indicated that Shuxuetong injection had anticoagulant effect， and would produce pharmacodynamics synergistic action when it was co-administrated with warfarin. Shuxuetong injection also decelerated the metabolism of warfarin， and resulted in pharmacokinetics interaction. Therefore， Shuxuetong injection could significantly increase anticoagulant effect of warfarin， indicating that the combination use of these two drugs should be refrained in order to avoid the risk of bleeding in clinical application. If they need to be used in combination， special attention should be paid to ensure the safety of patients.