疏血通注射液對大鼠體內(nèi)華法林抗凝作用的影響

趙海峰+孫佳慧+劉爽+劉艷+劉高峰

[摘要]研究疏血通注射液對大鼠體內(nèi)華法林抗凝作用的藥效學(xué)和藥動學(xué)影響，為臨床合理用藥提供參考。進行單劑量華法林研究時，將Wistar大鼠隨機分成空白對照組（A組）、疏血通注射液給藥組（B組）、華法林對照組（C組）、疏血通注射液與華法林聯(lián)合給藥組（D組）；進行穩(wěn)態(tài)華法林研究時，將Wistar大鼠隨機分成華法林對照組（E組）、疏血通注射液與華法林聯(lián)合給藥組（F組）。用血凝分析儀測定凝血酶原時間（PT）和活化部分凝血活酶時間（APTT），并計算國際標(biāo)準(zhǔn)化比值（INR），進行疏血通注射液對單劑量和穩(wěn)態(tài)華法林藥效學(xué)影響的研究；用UPLC-MS/MS聯(lián)合手性色譜柱技術(shù)測定r-華法林和s-華法林的血藥濃度，并計算大鼠體內(nèi)藥代動力學(xué)參數(shù)，研究疏血通注射液對單劑量和穩(wěn)態(tài)華法林的藥動學(xué)影響。單劑量華法林實驗結(jié)果顯示，疏血通注射液本身可使大鼠的PT，INR顯著升高（P<0.01），APTT升高（P<0.05）；與華法林聯(lián)用后，與華法林對照組相比，PT，INR顯著升高（P<0.01），APTT升高（P<0.05），s-華法林和r-華法林的藥動學(xué)參數(shù)C_max，AUC0-t，AUC0-∞均升高，t1/2延長，CL/F降低。穩(wěn)態(tài)華法林實驗結(jié)果顯示，與疏血通注射液聯(lián)用后，華法林的PT，INR顯著升高（P<0.01），s-華法林和r-華法林的血藥濃度均升高。該研究結(jié)果表明，疏血通注射液本身具有抗凝血作用，與華法林聯(lián)用可產(chǎn)生藥效學(xué)協(xié)同作用；兩藥聯(lián)用還可減慢華法林的代謝，產(chǎn)生藥動學(xué)相互作用。疏血通注射液可明顯增強華法林的抗凝作用，提示臨床用藥時應(yīng)盡量避免兩藥聯(lián)合應(yīng)用，以降低出血風(fēng)險，如必須聯(lián)用，應(yīng)密切監(jiān)測，以保障患者用藥安全。

[關(guān)鍵詞] 華法林； 疏血通注射液； 藥物相互作用； 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.