扶正化瘀方对正常及肝纤维化大鼠体内CYP450酶的影响(1)
[摘要]使用Cocktail探针药物法，研究扶正化瘀方(FZHY)对正常和肝纤维化大鼠细胞色素P450(CYP450)5种同工酶的影响。正常和二甲基亚硝胺(dimethylnitrosamine，DMN)腹腔注射诱导的肝纤维化模型大鼠，以FZHY浸膏粉连续灌胃2周后，单剂量尾静脉注射由CYP4505种同工酶的特异性探针底物非那西丁(CYP1A2)、甲苯磺丁脲(CYP2C9)、奥美拉唑(CYP2C19)、氢溴酸右美沙芬(CYP2D6)和咪达唑仑(CYP3A4)配置的Cocktail探针溶液后，通过建立的LC-MS/MS法同时检测血浆中5种探针药物的浓度，采用PKsolution2TM对数据进行处理，并计算主要药动学参数。正常大鼠灌胃FZHY后，非那西丁、甲苯磺丁脲、奥美拉唑和氢溴酸右美沙芬的AUC0-t均出现不同程度的增加，CL也均出现降低趋势，提示FZHY能明显抑制正常大鼠CYP1A2，CYP2C9，CYP2C19，CYP2D6的活性，但对CYP3A4的活性影响不明显;肝纤维化大鼠灌胃FZHY后，甲苯磺丁脲的AUC0-t显著增加，Vd显著降低，其他4种探针药物的药动学参数未见显著改变，提示在肝纤维化大鼠体内FZHY仅对CYP2C9有抑制作用，对CYP1A2，CYP2C19，CYP2D6，CYP3A4活性影响不明显。CYP450酶在肝纤维化条件下活性的改变可能是FZHY对正常和肝纤维化大鼠CYP450酶影响不同的原因。
, 百拇医药
[关键词]扶正化瘀方;Cocktail;CYP450同工酶;肝纤维化
EffectofFuzhengHuayurecipeonCYP450isozymes
innormalandliverfibrosisrats
ZHENGTian-hui1，2，LIUWei/1，LIShu-ping/1，YANGTao/1，WANGChang-hong/1，LIUCheng-hai1，2，4*
(1.SchoolofPharmacy，EastChinaUniversityofScienceandTechnology，Shanghai200237，China;
2.InstituteofLiverDiseases，ShuguangHospitalAffiliatedtoShanghaiUniversityofTraditionalChineseMedicine，Shanghai201203，China;
, 百拇医药
3.InstituteofChineseMateriaMedica，ShanghaiUniversityofTraditionalChineseMedicine;KeyLaboratoryfor
StandardizationofTraditionalChineseMedicinesunderMinistryofEducation，TraditionalKeyLaboratoryforNew
ResourcesandComprehensiveQualityStandardEvaluationofTraditionalChineseMedicines，Shanghai201203，China;
4.E-InstituteofInternalMedicineofTraditionalChineseMedicine，ShanghaiMunicipalEducationCommission，Shanghai201203，China)
, 百拇医药
[Abstract]TostudytheeffectofFuzhengHuayurecipe(FZHY)onfivetypesofisozymesofcytochromeP450(CYP450)ofnormalandliverfibrosisratsbyusingthecocktailprobemethod.Dimethylnitrosamine(DMN)wasinjectedtoinducetheliverfibrosismodel.AfterthetailveininjectionwithCocktailprobesolutionspreparedwithfiveCYP450sprobesubstrates(phenacetin-CYP1A2，omeprazole-CYP2C9，tolbutamide-CYP2C19，dextromethorphan-CYP2D6，midazolam-CYP3A4)，theplasmaconcentrationsofthefiveprobesubstratesweredeterminedbyLC-MS/MS，andthepharmacokineticparameterswerecalculatedbyPKsolutions2.AftertheoraladministrationwithFZHY，normalratsgivenphenacetin，omeprazole，tolbutamideanddextromethorphanshowedincreaseinAUC0-tanddecreaseinCLtovaryingdegrees，indicatingthatFZHYobviouslyinhibitedtheactivitiesofCYP1A2，CYP2C9，CYP2C19andCYP2D6innormalrats，butwithnoobviouseffectontheactivityofCYP3A4.AftertheoraladministrationwithFZHY，liverfibrosisratstreatedwithCYP2C9showedthesignificantincreaseinAUC0-tandsignificantdecreaseinVd，butwithnoobviouschangesinthepharmacokineticparametersofotherfourtypesofprovesubstances，suggestingthatFZHYcouldsignificantlyinhibittheactivityofCYP2C9inratsbuthadnoeffectontheactivitiesofCYP1A2，CYP2C19，CYP2D6andCYP3A4.ThechangesintheactivityofCYP450isozymesinliverfibrosisratsmaybethereasonforFZHY′sdifferenteffectsonCYP450isozymesinnormalandliverfibrosisrats., 百拇医药(郑天慧 刘伟 李淑萍 杨涛 王长虹 刘成海)
, 百拇医药
[关键词]扶正化瘀方;Cocktail;CYP450同工酶;肝纤维化
EffectofFuzhengHuayurecipeonCYP450isozymes
innormalandliverfibrosisrats
ZHENGTian-hui1，2，LIUWei/1，LIShu-ping/1，YANGTao/1，WANGChang-hong/1，LIUCheng-hai1，2，4*
(1.SchoolofPharmacy，EastChinaUniversityofScienceandTechnology，Shanghai200237，China;
2.InstituteofLiverDiseases，ShuguangHospitalAffiliatedtoShanghaiUniversityofTraditionalChineseMedicine，Shanghai201203，China;
, 百拇医药
3.InstituteofChineseMateriaMedica，ShanghaiUniversityofTraditionalChineseMedicine;KeyLaboratoryfor
StandardizationofTraditionalChineseMedicinesunderMinistryofEducation，TraditionalKeyLaboratoryforNew
ResourcesandComprehensiveQualityStandardEvaluationofTraditionalChineseMedicines，Shanghai201203，China;
4.E-InstituteofInternalMedicineofTraditionalChineseMedicine，ShanghaiMunicipalEducationCommission，Shanghai201203，China)
, 百拇医药
[Abstract]TostudytheeffectofFuzhengHuayurecipe(FZHY)onfivetypesofisozymesofcytochromeP450(CYP450)ofnormalandliverfibrosisratsbyusingthecocktailprobemethod.Dimethylnitrosamine(DMN)wasinjectedtoinducetheliverfibrosismodel.AfterthetailveininjectionwithCocktailprobesolutionspreparedwithfiveCYP450sprobesubstrates(phenacetin-CYP1A2，omeprazole-CYP2C9，tolbutamide-CYP2C19，dextromethorphan-CYP2D6，midazolam-CYP3A4)，theplasmaconcentrationsofthefiveprobesubstratesweredeterminedbyLC-MS/MS，andthepharmacokineticparameterswerecalculatedbyPKsolutions2.AftertheoraladministrationwithFZHY，normalratsgivenphenacetin，omeprazole，tolbutamideanddextromethorphanshowedincreaseinAUC0-tanddecreaseinCLtovaryingdegrees，indicatingthatFZHYobviouslyinhibitedtheactivitiesofCYP1A2，CYP2C9，CYP2C19andCYP2D6innormalrats，butwithnoobviouseffectontheactivityofCYP3A4.AftertheoraladministrationwithFZHY，liverfibrosisratstreatedwithCYP2C9showedthesignificantincreaseinAUC0-tandsignificantdecreaseinVd，butwithnoobviouschangesinthepharmacokineticparametersofotherfourtypesofprovesubstances，suggestingthatFZHYcouldsignificantlyinhibittheactivityofCYP2C9inratsbuthadnoeffectontheactivitiesofCYP1A2，CYP2C19，CYP2D6andCYP3A4.ThechangesintheactivityofCYP450isozymesinliverfibrosisratsmaybethereasonforFZHY′sdifferenteffectsonCYP450isozymesinnormalandliverfibrosisrats., 百拇医药(郑天慧 刘伟 李淑萍 杨涛 王长虹 刘成海)