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目的:研究丹红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及其作用机制,为临床合理用药提供参考。方法:Wistar大鼠随机分为空白对照组(Ⅰ)、丹红注射液给药组(Ⅱ)、华法林对照组(Ⅲ)和丹红注射液与华法林联合给药组(Ⅳ),每组8只。四组大鼠连续14d腹腔注射给予生理盐水或丹红注射液。在第8天,Ⅰ、Ⅱ组给予生理盐水灌胃1次,Ⅲ、Ⅳ组给予等量华法林溶液。分别于给药后的既定时间点采血,测定凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)值,计算国际标准化比值(INR),采用UPLC-MS/MS法测定S-华法林和R-华法林的血药浓度并计算相关药动学参数。结果:丹红注射液能升高大鼠的PT和INR值(P<0.01),与华法林合用能使大鼠PT和INR值显著增加(P<0.01),APTT值升高(P<0.05)。联合给药组与华法林对照组比较,S-华法林的C_(max)、AUC_(0-t)、AUC_(0-∞)分别增加了90.72%、52.17%、43.13%(P<0.01),t_(1/2)增加了14.76%(P<0.05);R-华法林的C_(max)、AUC_(0-t)、AUC_(0-∞)分别增加了56.89%、79.10%、77.96%(P<0.01),t_(1/2)增加了17.17%(P<0.05)。结论:丹红注射液与华法林联合应用时会增加华法林的抗凝作用,出血风险增加,应避免联合使用,或注意密切监测。
Objective: To study the effect of Danhong injection on pharmacodynamics and pharmacokinetics of warfarin in rats and its mechanism of action, and to provide a reference for clinical rational drug use. Methods: Wistar rats were randomly divided into blank control group (Ⅰ), Danhong injection group (Ⅱ), warfarin control group (Ⅲ) and Danhong injection combined with warfarin (Ⅳ) , Each group of 8. Four groups of rats were injected intraperitoneally with normal saline or Danhong injection for 14 days. On the 8th day, the rats in group Ⅰ and Ⅱ were given gavage once a day, while those in group Ⅲ and Ⅳ were given equal amount of warfarin solution. The blood samples were collected at different time points after administration to determine the prothrombin time (PT) and activated partial thromboplastin time (APTT) values, and calculate the international normalized ratio (INR). The UPLC-MS / Fahrenheit and R-warfarin plasma concentrations and calculate the relevant pharmacokinetic parameters. Results: Danhong injection can increase the PT and INR of rats (P <0.01), and increase the PT and INR of rats with warfarin (P <0.01) and increase the APTT (P <0.05) ). Compared with warfarin control group, Cmax, AUC_ (0-t), AUC_ (0-∞) of S-warfarin increased by 90.72%, 52.17% and 43.13% 0.01), and the t_ (1/2) increased by 14.76% (P <0.05). The C_max, AUC_0_t and AUC_0_∞ of R-warfarin increased by 56.89% and 79.10% %, 77.96% (P <0.01), t_ (1/2) increased by 17.17% (P <0.05). Conclusion: Danhong injection combined with warfarin will increase the anticoagulant effect of warfarin, the risk of bleeding increased, should be avoided in combination, or pay close attention to the close monitoring.