Effects Of Panax Notoginseng On Pharmacokinetic Of Warfarin And Its Mechanism

Warfarin is the most commonly used oral anticoagulant in clinical practice.However,due to the narrow treatment window of warfarin and the great difference in individual drug administration,it is easy to interact with other drugs and food,and thus easy to produce adverse drug reactions.Warfarin treatment is particularly challenging in China for two reasons.Firstly,because Chinese patients are more sensitive to warfarin than caucasians,the maintenance dose required is 40-50%lower than caucasians.Secondly,in China,people often like to use Chinese herbal medicine for tonic food or use a combination of traditional Chinese medicine and medicine to treat diseases.ObjectiveTake Panax notoginseng as an example to explore the possible mechanism of traditional Chinese medicine's effect on warfarin anticoagulant therapy.MethodThe drug administration model of SD rats was established and blood was collected at different time points.Prothrombin Time?PT?was measured with the Prothrombin Time assay kit,and the International Normalized Ratio?INR?was calculated for pharmacodynamic evaluation.At the same time,High Performance Liquid Chromatography?HPLC?was established and applied to determine the warfarin plasma concentration for pharmacokinetic evaluation.In vitro?Hep G2cells?and in vivo?SD rats?models were established to investigate the possible mechanism of the interaction between Panax Notoginseng Saponins and warfarin through the expression of CYP1A2,CYP3A4 and CYP2C9.Results1.By comparison of the INR of warfarin group,it was found that the group of warfarin combine Panax notoginseng are significantly higher than warfarin group?P<0.05?at 24,48,72h.The mean values of INR were 1.51,2.08,2.29 and 3.70 at24 h.The mean values of INR were 1.40,2.49,3.34 and 4.46 at 48 h.The mean values of INR were 1.58,2.74,4.30 and 6.61 at 72 h.By comparison of the blood concentration of warfarin of control group,it was only found that the groups of warfarin combine Panax notoginseng with middle and hight dosage are significantly higher than control group?P<0.05,P<0.001 respectively?.The results of pharmacokinetic study showed that the Panax notoginseng could enhance the AUC,AUMC,MRT,t_1/2 and C_maxax of warfarin in rats.2.At 24h and 48h,the INR of the warfarin combine PNS with middle and hight dosage group was statistically significant compared with that of the warfarin group?P<0.05?.The mean values of INR were 1.63,1.82,1.97 at 24h and 1.571.88,2.01 at 48 h.At 72 h after administration,warfarin+PNS?low,medium and high dosage?group had statistical significance?P<0.05?.The mean INR values were 1.53,1.71,1.90 and 1.96,respectively.According to the results of detection of blood concentration,it was found that the blood concentration of warfarin combine PNS with hight dosage group are significantly higher than control group?P<0.05?at 4,8,12,24,48,72 h after the administration.Warfarin combine PNS with low and middle dosage group compared to warfarin group some blood collection points also have statistical significance?P<0.05?.Pharmacokinetic studies show that PNS can enhance AUC_0-t,AUMC_0-t and reduce CLz/F of warfarin in rats.It indicated that the combination of PNS and warfarin may increase the exposure of warfarin in rats.3.The expression of CYP2C9 in Hep G2 cells and rat liver tissues indicated that both of PNS group and the combination of PNS and warfarin group had no effect on the expression of CYP2C9.Compared with the warfarin group,the expression of CYP3A4 in Hep G2 cells and rat liver tissues was significantly down-regulated?P<0.05?,suggesting that the combination of warfarin and PNS may inhibit the expression of CYP3A4 protein.In the Hep G2 cell experiment,the expression of CYP3A4 was significantly down-regulated in the PNS group compared with the control group?P<0.001?,suggesting that PNS may inhibit the expression of CYP3A4.Warfarin in combination with medium dosage PNS compared to warfarin group can induce CYP1A2 expression.When warfarin was combined with high-dosage PNS compared to warfarin group,there was no difference in the expression of CYP1A2.ConclusionWarfarin combined with a certain amount of Panax notoginseng can enhance the efficacy of warfarin.PNS may be one of the main components of Panax Notoginseng to enhance warfarin's anticoagulant effect.The mechanism may be that PNS inhibit the expression of CYP3A4,thereby reducing warfarin metabolism and enhancing anticoagulation effect.