Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes

doi:10.1038/s41401-021-00692-7

	Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes
	Wu, Ya-li 1,2; Xue, Ya-ru 1; Guo, Zi-tao 1; Chen, Zhen-dong 1; Ge, Xin-yu 1; Zhong, Da-fang 1,2; Diao, Xing-xing 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2021-05-25
页码	10
关键词	furmonertinib (alflutinib AST2818) quantitative proteomics sandwich-cultured human hepatocytes
ISSN号	1671-4083
DOI	10.1038/s41401-021-00692-7
通讯作者	Zhong, Da-fang(dfzhong@simm.ac.cn) ; Diao, Xing-xing(xxdiao@simm.ac.cn)
英文摘要	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 mu M rifampin expressed 20.16 +/- 5.78 pmol/mg total protein, whereas the cells induced with 0.5 mu M 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 mu M furmonertinib (3.79 +/- 0.52).
资助项目	National Natural Science Foundation of China[81903701]
WOS关键词	TANDEM MASS-SPECTROMETRY ; INTERINDIVIDUAL VARIABILITY ; METABOLIZING-ENZYMES ; HEPATIC EXPRESSION ; LC-MS/MS ; QUANTIFICATION ; RAT ; PROTEIN ; PROTEOMICS ; ISOFORMS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000654149400002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297386]
专题	中国科学院上海药物研究所
通讯作者	Zhong, Da-fang; Diao, Xing-xing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Wu, Ya-li,Xue, Ya-ru,Guo, Zi-tao,et al. Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes[J]. ACTA PHARMACOLOGICA SINICA,2021:10.
APA	Wu, Ya-li.,Xue, Ya-ru.,Guo, Zi-tao.,Chen, Zhen-dong.,Ge, Xin-yu.,...&Diao, Xing-xing.(2021).Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes.ACTA PHARMACOLOGICA SINICA,10.
MLA	Wu, Ya-li,et al."Furmonertinib (Alflutinib, AST2818) is a potential positive control drug comparable to rifampin for evaluation of CYP3A4 induction in sandwich-cultured primary human hepatocytes".ACTA PHARMACOLOGICA SINICA (2021):10.