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1、-Results1.TheestablishedRP-HPLC-UAplasmaconcentrationsofwarfarin,diazepamasinternalstandard,retentiontime12.8min。TheregressionequationaofstandardcurvewasYˆ=0.1444X+1.0264(r=0.9994),overtherangeof48.0～2500.0ng·mL-1.Thedetectionlimitwas16ng·mL-1(S/N＞3).Recoveries101%-103%
2、.Theintra-andinter-dayRSDwerelessthan2.10%.2.TheresultsofgenotypingCYP2C9andVKORC1ofthe73patientsisCYP2C9*1/*1,63cases;*1/*3,10cases;VKORC1-1639AA,62cases,GA,10cases；GG,onecase.3.Basedon190concentrations、263INRmonitoringvaluesandotherinformationofthe73patients,thewarfar
3、inpopulationpharmacokinetics/pharmacodynamicsfinalmodelishhCL(WT/60)e=q××q×WTCLCLCYP（ifCYP2C9*1/*1，θCYP=1；if*1/*3，θCYP=0.708）hECe=q×q×（ifVKORC1-1639AA，θEC50VKOR=1；ifGA，θVKOR=2.01）50ECVKOR50V=q；VK=q；E0KE0E=q；maxEmaxE=q×ehE00E0Amongthem,thepatient'sweight,CYP2C9andVKORC1g
4、enotypearemajorinfluencefactorsinwarfarinpharmacokinetic/pharmacodynamicparameters.4.Modelfittingresultsshowsthegoodnessfitofthefinalmodel.GoodnessoffitforPlasmaconcentrationsandINRsuperiorthanthesimplestmodel.Theestimatedvalueoffinalmodelwasinthe95%CIbyBootstrapmethoda
5、ndrelateddeviationswerelessthan6.30%.NPDEshowedhomogeneityofvarianceandanormaldistribution.Conclusion1.TheestablishedRP-HPLC-UVmethodisaccurate,reproducible,andsimple,----suitablefortheconcentrationsdeterminationofwarfarininhumanplasmaandstudydrugaction.-5-万方数据----1.Wei
6、ght,CYP2C9andVKORC1genotypingarethemainfactorsthataffectwarfarinPK/PDparameters.2.TheestablishedwarfarinpopulationPK/PDmodelisstableandeffectiveandofgoodgoodnessandpredictiveability,canprovideareferencetodevelopindividualizeddosingregimens.KeywordWarfarin;plasmaconcentr
7、ation;HPLC;PCR-RFLP;CYP2C9;VKORC1;NONMEM;Populationpharmacokinetics/pharmacodynamics-6-----万方数据----前言华法林(warfarin)为香豆素类口服抗凝药，是维生素K拮抗剂，通过抑制肝脏维生素K环氧化物还原酶，导致无活性的氧化型维生素K无法激活为还原型，进而抑制维生素K参与的凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ在肝脏的合成，以发挥抗凝作用。目前被广泛应用于瓣膜病、瓣膜置换术后、非瓣膜病性房颤、肺栓塞和深静脉血栓等的治疗[1]。国际标准化比值(Interna
8、tionalnormalizedratio,INR)是监测华法林抗凝疗效的首选指标。华法林治疗窗窄，存在抗凝不足导致血栓形成或抗凝过度引起出血等风险，甚至危及患者生命。同时，影响华法林疗效的因素很多，其稳定剂量在不同种族
