Ginkgo Biloba Extract To Human Warfarin Drug Action And Pharmacodynamics

OBJECTIVES To study the effect of Ginkgo biloba extract on the pharmacodynamics and pharmacokinetics of warfarin,and to assess whether or not Ginkgo biloba extract alone has any effect on main blood clotting indexes.METHODS1.Dose administrationA randomized,double-blind,placebo-controlled,two-way cross-over trial was designed.Healthy volunteers(n=12, sex rario=1:1)were randomized to receive either Ginkgo biloba extract in the first treatment period and placebo in the second treatment period or vice versa.In addition to their randomized trentment,all volunteers received a single dose of 5 mg warfarin on day 29 of each treatment period.2.Blood samples collection2.1 Samples for determination of warfarinWe collected Samples before and at 0.25,0.5,0.75,1,1.5,2,4,8, 12,24,36,48,72,96,120,144h after dose of warfarin, in heparinized centrifuge tubes and then separated by centrifuging and stored at -80℃for detection.2.2 Samples for determination of main blood clotting indexesWe collected samples before dose of EGB,before dose of warfarin and at 4,8,12,24,36,48,72,96,120,144 h after dose of warfarin, in vacuum-collected tubes containing sodium citrate solution and then separated by centrifuging and stored at -80℃for detection.3.Sample analysis3.1 Plasma concentration of warfarin was determined by HPLC-UV.3.2 Plasma samples of main blood clotting indexes was determined by semi-automated coagulation analyzer.RESULTS1.Determination of warfarinThe calibration curve was linear in the range of 25.0-2000.0 ng·mL-1 for warfarin(R2=0.9996) and the lower limit of quantitation was 25.0 ng·mL-1. The extraction recoveries were within 65%-85%. The method recoveries were within 85%-115%, intra-and inter-day RSDs were all less than 10%.2.The effect of EGB on the Pharmacodynamics of WarfarinCoadministered with EGB,the main Pharmacodynamic parameters of warfarin are as follows:Cmax:729.6±152.1 ng·mL-1, AUC0→144:27557.2±2834.0 ng·h·mL-1, AUC0→∞:36402.0±5551.2ng·h·mL-1, t1/2:76.6±28.4h, CL/F: 0.15±0.03 L·h-1, V/F:15.2±4.3 L。Coadministered with placebo,the main Pharmacodynamic parameters of warfarin are as follows:Cmax:633.2±122.5 ng·mL-1, AUC0→144: 25614.2±3418.4ng·h·mL-1,AUC/C0→∞:32403.0±5230.2 ng·h·mL-1, t1/2:55.1±11.2 h, CL/F:0.16±0.01 L·h-1, V/F:12.9±3.5L。3.The effect of EGB on the Pharmacokinetics of WarfarinCoadministered with EGB,the main Pharmacokineticic indexes of warfarin are as follows:PT Emax:12.9±0.7 s,PT AUC0→t:1887.3±50.1s·h, APTT Emax: 36.1±1.2s, APTT AUC0→t:4910.2±149.4 s·h,TT AUC0→t:1635.4±111.2 s·h。Coadministered with placebo,the main Pharmacokineticic indexes of warfarin are as follows:PT Emax:13.7±0.5 s,PT AUC0→t:1846.2±57.1 s·h, APTT Emax:37.3±2.2 s, APTT AUC0→t:4950.2±189.4 s·h, TT AUC0→t: 1539.3±96.1 s·h。 CONCLUEGBNS1.Administration of EGB significantly increased Cmax,AUC0→144,AUC0→∞,t1/2 and significantly decreased CL/F of Warfarin compared with placebo.2.EGB had no clinically significant effect on the pharmacodynamic effects of Warfarin, as assessed 144h after Warfarin dosing by measurement of prothrombin time, activated partial thromboplastin time, thrombin time.