Effects of cefoperazone-sulbactam on the pharmacokinetics and pharmacodynamics of warfarin in rats
AIM:To elucidate the effects of cefo-perazone-sulbactam on the pharmacokinetics of warfarin and the mechanism behind the enhance-ment of warfarin's efficacy.METHODS:Thirty-two rats were randomly assigned to four groups:WN(healthy rats after the gastric-administration of 0.125 mg/kg warfarin),WCN(healthy rats after the gastric-administration of 0.125 mg/kg warfarin and 0.3 g/kg cefoperazone-sulbactam),WO(a rat mod-el of biliary drainage after the gastric-administra-tion of 0.125 mg/kg warfarin),WCO(a rat model of biliary drainage after the gastric-administration of 0.125 mg/kg warfarin and 0.3 g/kg cefoperazone-sulbactam).Blood samples were collected at vari-ous time points from the femoral artery to deter-mine the plasma concentration of warfarin and from the tail vein to measure the International Nor-malized Ratio(INR).Warfarin levels were quanti-fied using LC/MS/MS,and pharmacokinetic param-eters were calculated using a non-compartmental model.The expression of P-glycoprotein(P-gp)in the ileal tissues of the WN and WCN groups was determined by Western blotting.RESULTS:Com-pared with the WN group,the WCN group demon-strated a significant increase in AUC0-t,Cmax,and Ka,and a notable decrease in CL/F,and INR values sig-nificantly increased.However,there was no signifi-cant difference in pharmacokinetic parameters and INR values between the WO group and the WCO group.Compared to the WN group,the WO group showed a significant reduction in AUC0-t,Cmax,and CL/F,with an obvious increase in t1/2.The INR of the WCN group was significantly higher than that of the WCO group after 6 hours.Western blotting re-sults indicated a 62.1％reduction in P-gp expres-sion in the ileum of the WCN group compared to the WN group(P＜0.01).CONCLUSION:Cefopera-zone-sulbactam significantly influences the pharma-cokinetic parameters of warfarin and enhances its pharmacological effect by inhibiting intestinal P-gp expression.Biliary drainage significantly affects the pharmacokinetics of warfarin rats,and there is no significant drug interaction between the two after biliary drainage.
万方数据
维普
