Study On The Effect Of Total Flavonoids From Galium Verum L.on Warfarin Pharmacokinetics And Pharmacodynamics In Rats

Objective:To investigate the effects of FGVL on the pharmacokinetics and pharmacodynamics of warfarin in rats and the effect of FGVL on the subtypes of CYP450,and to explore the pharmacokinetics and pharmacodynamics of FGVL versus warfarin from the perspective of metabolism.The mechanism of the impact is to provide the reasonable basis to clinical application of the two drugs and the FGVL with the same drug-metabolizing enzyme substrates.Methods:HPLC method was used to determine the plasma concentration of warfarin in rats.The pharmacokinetic parameters of warfarin and FGVL combined with warfarin were calculated and compared.The main pharmacokinetic parameters,PT and INR,were determined by the coagulation method in Different drug group.The coagulation method was used.The main pharmacodynamic parameters,PT and INR,were determined for the single drug group and the combination group.The plasma concentration of the probe drug was determined by HPLC and its pharmacokinetic parameters were calculated to evaluate the effect of FGVL on the activity of subtypes of CYP450 enzyme in rats and the results were analyzed based on the Cocktail probe drug method.Results:Compared with the pharmacokinetic parameters of the individual drug group,the t1/2 of the combination group was significantly shortened,the AUC0～t and AUC0-∞ were significantly decreased,and the CL was significantly increased(P<0.05);Taking into account the pharmacodynamic parameters of each group,FGVL significantly changed the PT and INR of warfarin in rats(P<0.05),and the PT and INR of the combination group significantly prolonged.Compared with the blank group,the t1/2,AUC0-t,AUC0-∞,MRT0-t,and MRT0-∞ in the low-dose and middle-dose caffeine groups was decreased significantly,CL increased significantly,and t1/2 AUC0-t,MRT0-t reduced significantly in high-dose caffeine group.AUC0-t in metoprolol was significantly decreased in low and middle dose groups,and AUC0-t and AUC0-∞ in metoprolol were significantly decreased in high dose group,and MRT0-∞ was significantly increased in the high dose group.The AUC0-t and MRT0-t of midazolam were significantly increased in the low dose group,the AUC0-t of midazolam was significantly decreased,MRT0-t was significantly increased in the middle dose group,and MRT0-t of midazolam was significantly increased in high dose group.The MRT0-t of tolbutamide was significantly increased in the low-dose group,the AUC0-t AUC0-∞ of middle-dose tolbutamide group was significantly reduced,and MRT0-∞ was significantly increased.In the high-dose tolbutamide group,t1/2,AUC0-∞,MRT0-t and MRT0-∞ was increased significantly,and CL was significantly decreased.Compared with the phenobarbital group,AUC0-t,MRT0-t was significantly increased in low-dose and high-dose group.Compared with the cimetidine group,MRT0-t was increased significantly in high-dose group.Conclusions:FGVL significantly affected the pharmacokinetics and pharmacokinetic parameters of warfarin in rats.The low,medium and high doses of FGVL induced CYP1A2 activity in rats,and the intensity was lower than that of phenobarbital.High dose of FGVL inhibited the CYP2C9 activity in rats,its intensity is higher than cimetidine group;Low and middle dose groups had no significant effect on CYP2C9 activity in rats;FGVL had no significant effect on CYP2D6,CYP2E1,and CYP3A4 activity in rats.Because warfarin is a substrate of CYP1A2,CYP2C9,and CYP3A4,and it is speculated that FGVL accelerates the metabolism of warfarin by affecting the activity of CYP1A2,and FGVL increases PT and INR in the combination group by prolonging PT.