mPEG-PLGA聚合物对大鼠肝脏CYP450酶活性的影响  

Effects of mPEG-PLGA polymer on activity of rat CYP450 isozymes in vitro

作　　者：邱丽慧[1] 斯陆勤[2] 涂坤[2] 吴琪[2] 李高[2] 黄建耿[2] 孙明辉[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院药学部,湖北武汉430030 [2]华中科技大学同济医学院药学院,湖北武汉430030

出　　处：《中国医院药学杂志》2016年第15期1276-1282,共7页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学基金(编号:81473170);湖北省自然科学基金项目(编号:2015CFB139)

摘　　要：目的：研究mPEG-PLGA聚合物对大鼠肝CYP450酶活性的影响。方法：采用芘荧光探针技术测定mPEG-PLGA聚合物的临界胶束浓度（CMC）,并用薄膜分散法制备mPEG-PLGA聚合物胶束;分别采用大鼠肝微粒体和原代大鼠肝细胞模型,将mPEG-PLGA聚合物溶液与CYP450酶特异性探针底物孵育,经液-质联用技术（LC-MS/MS）检测代谢产物,通过比较代谢产物生成量的变化,评价聚合物对CYP450酶的抑制和诱导作用。结果：mPEG-PLGA聚合物的CMC为5.37μg·mL^-1;mPEG-PLGA聚合物浓度低于CMC时对大鼠肝CYP450酶无抑制作用;当聚合物胶束质量浓度≥100μg·mL-1时显示有抑制作用,且呈现浓度依赖性。mPEG-PLGA聚合物对CYP1A1/B2、CYP1A2、CYP2B1、CYP2C6、CYP2C11、CYP2D2、CYP3A1/2（底物为咪达唑仑）、CYP3A1/2（底物为睾酮）7种酶亚型的IC50值分别为1.13,2.37,2.38,1.77,1.32,1.17,1.12,0.91 mg·mL^-1,其中对CYP3A1/2的抑制作用最为明显。mPEG-PLGA聚合物在0.1～1 000μg·mL-1质量浓度范围对CYP1A2酶均有诱导作用,且在高质量浓度1 000μg·mL-1时最强（P〈0.001）;而该聚合物仅在0.1μg·mL-1时对CYP2B1、CYP2C6和CYP3A1/2酶呈现诱导作用（P〈0.05）。结论：mPEG-PLGA聚合物对大鼠肝脏CYP450酶亚型活性有一定的抑制和诱导作用,其抑制和诱导作用程度与酶亚型种类和聚合物浓度有关。OBJECTIVE To study effects of mPEG-PLGA polymer on activity of rat CYP450 isozymes in vitro.METHODS Critical micelle concentration（CMC）of mPEG-PLGA polymer was determined by fluorescence probe technique with pyrene.Micelles were prepared by thin film hydration method.mPEG-PLGA polymer was incubated at a series of concentration levels with specific probe substrates of CYP450 isozymes in both rat liver microsomes and primary hepatocytes.Inhibitory and inductive effects of mPEG-PLGA polymer on activity of CYP450 isozymes were evaluated by analyzing metabolites using a robust liquid mass spectrometry（LC-MS/MS）assay.RESULTS CMC value of mPEG-PLGA polymer was 5.37μg·mL^-1.When mPEG-PLGA polymer concentrations were≥100μg·mL^-1,significant inhibitory effects were produced on CYP450 enzymes in a concentration-dependent manner.However,no change was observed below CMC.IC50 values of mPEG-PLGA polymer on seven isozymes（CYP1A1/B2,CYP1A2,CYP2B1,CYP2C6,CYP2C11,CYP2D2,CYP3A1/2）were 1.13,2.37,2.38,1.77,1.32,1.17,1.12（substrate for midazolam）,0.91（substrate for testosterone）mg·mL^-1,respectively,with strongest inhibition observed on CYP3A1/2.The mPEG-PLGA polymer showed obvious induction on CYP1A2,especially at the highest concentration（1000μg·mL^-1）（P〈0.001）,while activities of CYP2B1,CYP2C6 and CYP3A1/2 enzymes were increased when concentration of mPEG-PLGA polymer was 0.1μg·mL^-1（P〈0.05）.CONCLUSION mPEG-PLGA polymer plays a certain role in both inhibition and induction of rat CYP450 isozymes activity,based on types of isozymes and concentrations of polymer.

关 键 词：mPEG-PLGA聚合物 CYP450 大鼠肝微粒体 原代大鼠肝细胞 抑制 诱导 

分 类 号：R96[医药卫生—药理学]