Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer
文献类型：期刊论文
| 作者 | Liu, Xiao-yun1,2; Guo, Zi-tao1; Chen, Zhen-dong1,2; Zhang, Yi-fan1 ; Zhou, Jia-lan1; Jiang, Yong3; Zhao, Qian-yu3; Diao, Xing-xing1,2; Zhong, Da-fang1,2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2020-03-31 |
| 页码 | 11 |
| ISSN号 | 1671-4083 |
| 关键词 | alflutinib AST5902 metabolism enzyme induction drug-drug interaction |
| DOI | 10.1038/s41401-020-0389-3 |
| 通讯作者 | Diao, Xing-xing(xxdiao@simm.ac.cn) ; Zhong, Da-fang(dfzhong@simm.ac.cn) |
| 英文摘要 | Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The E-max of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 mu M) were 7.22-, 19.4- and 9.46-fold, respectively. The EC50 of alflutinib-induced CYP3A4 mRNA expression was 0.25 mu M, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug-drug interactions are expected during alflutinib treatment. |
| WOS关键词 | CELL LUNG-CANCER ; DRUG-DRUG INTERACTIONS ; OPEN-LABEL ; 1ST-LINE TREATMENT ; OSIMERTINIB ; GEFITINIB ; DACOMITINIB ; MUTATIONS ; ERLOTINIB |
| 资助项目 | Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306] ; National Natural Science Foundation of China[81521005] ; National Natural Science Foundation of China[81903701] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000522605300001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/280908]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Diao, Xing-xing; Zhong, Da-fang |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shanghai Allist Pharmaceut Inc, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Xiao-yun,Guo, Zi-tao,Chen, Zhen-dong,et al. Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer[J]. ACTA PHARMACOLOGICA SINICA,2020:11. |
| APA | Liu, Xiao-yun.,Guo, Zi-tao.,Chen, Zhen-dong.,Zhang, Yi-fan.,Zhou, Jia-lan.,...&Zhong, Da-fang.(2020).Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer.ACTA PHARMACOLOGICA SINICA,11. |
| MLA | Liu, Xiao-yun,et al."Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer".ACTA PHARMACOLOGICA SINICA (2020):11. |
入库方式： OAI收割
来源：上海药物研究所
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