刺五加注射液对大鼠华法林抗凝作用的影响

摘要

Objective To study the effects of ciwujia injection on the pharmacodynamics and pharmacokinet-ics of warfarin in rats, and to provide reference for rational drug use of combination therapy. Methods Wistar rats were randomly divided into four groups,blank control group (group A),ciwujia injection group (group B),warfarin control group ( group C) ,warfarin combined ciwujia injection group ( group D) ,eight rats in each group. The rats of four group swere administered physiological saline or ciwujia injection (15 mL/kg) by caudal vein for 14 consecutive days. On the 8th day,rats in group A and group B were orally administered with the same dose of physiological saline, and rats in group C and group D were orally administered with warfarin solution ( 0. 2 mg/kg ) . The blood samples were collected from the caudal veins at different time points. The prothrombintime ( PT) and activated partial thrombo-plastin time ( APTT) of the blood samples were determined by coagulation analyzer,and the blood concentrations of S-warfarin and R-warfarin were determined by UPLC-MS/MS. Pharmacokinetic parameters were calculated by DAS 2. 0 software. Results Ciwujia injection had no effect on PT,APTT and INR,but ciwujia injecion combined with warfarin could increase the blood concentrations of warfarin (including S-type and R-type,P<0. 05 or P<0. 01)and the valne of PT and INR significantly (P<0. 05 or P<0. 01). Conclusion Ciwujia injection could decrease the metabolism of warfarin ( including S-type and R-type) ,and increase the anticoagulant effect. Therefore,the combination use of the two drugs should be refrained,in order to avoid the risk of bleeding. Special monitoring should be carried out if the combi-nation therapy is used.%目的 研究刺五加注射液对大鼠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. 方法 将Wistar雄性大鼠随机分成空白对照组( A组)、刺五加注射液给药组( B组)、华法林对照组( C组)、华法林-刺五加注射液联合给药组(D组),4 组大鼠连续腹腔注射生理盐水或刺五加注射液(15 mL/kg) 14 d. 第8天,A、B两组灌胃给予相同剂量的生理盐水,C、D两组灌胃给予华法林溶液(0.2 mg/kg),并于设定的一系列时间点取血. 用血凝分析仪测定凝血酶原时间( PT)、活化部分凝血活酶时间( APTT) ,并计算国际标准化比值( INR). 用UPLC-MS/MS法联合手性色谱柱技术测定血浆中华法林(包括S-型和R-型)浓度,用 DAS 2. 0软件计算药代动力学参数. 结果 刺五加注射液对PT、APTT及INR无明显影响;与华法林对照组比较,合用刺五加注射液后,华法林(包括S-型和R-型)的药动学参数Cmax、AUC0-t和AUC0-∞等显著升高( P<0. 05或P<0. 01),药效学参数PT及INR显著增加(P<0. 05或P<0. 01). 结论 刺五加注射液可减慢华法林(包括S-型和R-型)的代谢,使华法林抗凝作用增强. 提示临床用药时应尽量避免两药联合应用,以避免出血风险,如必须联用,应密切监测.