The Effect Of Ginsenosides On Pharmacological Function Of Warfarin In Rats

Objective:Ginseng as a traditional Chinese herbal medicine with the effects of replenishing qi and activating blood,can protect the cardiovascular and enhance the body’s immunity,is widely applied to treat cardiovascular and cerebrovascular diseases and preventive health care.Warfarin,as a widely used drug,been used to prevent and treat a number of thromboembolic disorders.Warfarin with the individual differences in drug use and will be easy interact with some Chinese and Western medicines.Ginseng may interact with warfarin for its complex chemical composition.We aimed at getting a conclusion and dose-and time-effect relationship about the effect of combination of ginsenosides and warfarin through a systematic study about pharmacological effects,drug metabolism,thrombosis,related proteins and genes.We provide a theoretical basis for the further clinical rational use of warfarin.Methods:We examined the change of prothrombin time(PT)and international normalized ratio(INR)at different continuous oral doses(0.2,0.3,0.4,0.5mg/kg)of warfarin to achieve the pharmacological effect of warfarin in clinical treatment(INR=2.0-3.0)in rats and the relationship between efficacy and time.The PT/INR and the level of thrombosis were evaluated by blood coagulation analyzer and tail thrombosis in a rat model to assess the pharmacodynamic of warfarin with different doses of genosinosides(30 mg/kg,100 mg/kg,300 mg/kg).The high-performance liquid chromatography-mass spectrometry measured the concentration of warfarin and the major metabolite 7-hydroxywarfarin to study the change of pharmacokinetic parameter and metabolic level of warfarin.Moreover,the expression of coagulation factor II,VII,protein Z and the gene of CYP1A2,CYP2C9,CYP3A4 were measued by enzyme linked immunosorbent assay and reverse transcription-PCR.Results:The experiment of different oral doses was performed at 0.4 mg/kg of warfarin would reach the clinical results.Warfarin exert anticoagulant effect after continuous oral for 3 days.Ginsenosides did not significantly alter the anticoagulant effect and the plasma concentration of warfarin after take ginsenosides and warfarin together for one week,but the pharmacodynamic of warfarin had decreased in second week and significantly decreased in the third week.Besides,the higher dose of ginsenosides,the closer of PT/INR to normal rats.And the ginsenosides represent time-dosage dependent relationship to reduce anticoagulant effect of warfarin.Ginsenosides can improve the elimination rate of warfarin in rat.The concentration of warfarin and 7-hydroxywarfarin showed a decrease and increase trend,and coagulation factors II,VII and protein Z close to normal levels.The longer drug combination,the higher doses of ginsenosides,the more significant of the result.Drug combination for three weeks,the expression level of CYP2C9 and CYP3A4 were increased by more than three times,and was positively correlated with the dose of ginsenosides.Conclusion:The present study indicates that,long-term use of ginsenosides can reduced the anticoagulant effect of warfarin.The higher doses of ginsenosides,the more significance of down-regulation.Moreover,ginsenosides can improve hepatic drug metabolizing enzyme gene CYP2C9 and CYP3A4 expression accelerate metabolism of warfarin to reduce its anticoagulant and antithrombotic effect.