典型文献
Furmonertinib(Alflutinib,AST2818)is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes
文献摘要：
Furmonertinib(Alflutinib,AST2818),as a third-generation epidermal growth factor receptor inhibitor with an advanced efficacy and a relatively wide safety window,has been commercially launched in China recently.However,previous clinical studies demonstrated its time-and dose-dependent clearance in a multiple-dose regimen.In vitro drug metabolism and pharmacokinetic studies have suggested that furmonertinib is mainly metabolized by cytochrome P450 3A4(CYP3A4)and can induce these enzymes via an increased mRNA expression.This study investigated two important evaluation criteria of CYP3A4 induction by furmonertinib through quantitative proteomics and probe metabolite formation:simultaneous(1)protein expression and(2)enzyme activity with sandwich-cultured primary human hepatocytes in the same well of cell culture plates.Results confirmed that furmonertinib was a potent CYP3A4 inducer comparable with rifampin and could be used as a positive model drug in in vitro studies to evaluate the induction potential of other drug candidates in preclinical studies.In addition,inconsistencies were observed between the protein expression and enzyme activities of CYP3A4 in cells induced by rifampin but not in groups treated with furmonertinib.As such,furmonertinib could be an ideal positive control in the evaluation of CYP3A4 induction.The cells treated with 10 μM rifampin expressed 20.16±5.78pmol/mg total protein,whereas the cells induced with 0.5 μM furmonertinib expressed 4.8±0.66 pmol/mg protein compared with the vehicle(0.1％dimethyl sulfoxide),which contained 0.65±0.45 pmol/mg protein.The fold change in the CYP3A4 enzyme activity in the cells treated with rifampin was 5.22±1.13,which was similar to that of 0.5 μM furmonertinib(3.79±0.52).
文献关键词：
中图分类号：
作者姓名：
Ya-li Wu;Ya-ru Xue;Zi-tao Guo;Zhen-dong Chen;Xin-yu Ge;Da-fang Zhong;Xing-xing Diao
作者机构：
State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201210,China;University of Chinese Academy of Sciences,Beijing 100049,China
文献出处：
引用格式：
[1]Ya-li Wu;Ya-ru Xue;Zi-tao Guo;Zhen-dong Chen;Xin-yu Ge;Da-fang Zhong;Xing-xing Diao-.Furmonertinib(Alflutinib,AST2818)is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes)[J].中国药理学报（英文版）,2022(03):747-756
A类：
Furmonertinib,Alflutinib,AST2818,rifampin,furmonertinib,78pmol
B类：
potential,positive,control,drug,comparable,evaluation,CYP3A4,induction,sandwich,cultured,primary,human,hepatocytes,third,generation,epidermal,growth,receptor,inhibitor,advanced,efficacy,relatively,wide,safety,window,has,been,commercially,launched,China,recently,However,previous,studies,demonstrated,its,dose,dependent,clearance,multiple,regimen,In,vitro,metabolism,pharmacokinetic,have,suggested,that,mainly,metabolized,by,cytochrome,P450,these,enzymes,via,increased,expression,This,study,investigated,two,important,criteria,through,quantitative,proteomics,probe,metabolite,formation,simultaneous,protein,activity,same,well,plates,Results,confirmed,was,inducer,could,used,model,evaluate,other,candidates,preclinical,addition,inconsistencies,were,observed,between,activities,cells,induced,but,not,groups,treated,such,ideal,expressed,total,whereas,compared,vehicle,dimethyl,sulfoxide,which,contained,fold,change,similar
AB值：
0.449646
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