Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans

doi:10.1038/s41401-021-00667-8

	Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans
	Meng, Jian 1; Zhang, Hua 3; Bao, Jing-jing 2; Chen, Zhen-dong 1; Liu, Xiao-yun 1; Zhang, Yi-fan 1; Jiang, Yong 2; Miao, Li-yan 3; Zhong, Da-fang 1
刊名	ACTA PHARMACOLOGICA SINICA
	2021-04-29
页码	10
关键词	metabolism mass balance distribution covalent binding furmonertinib
ISSN号	1671-4083
DOI	10.1038/s41401-021-00667-8
通讯作者	Zhong, Da-fang(dfzhong@simm.ac.cn)
英文摘要	Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 mu Ci/81.5 mg [C-14]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a t(max) of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t(1/2) of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 mu Ci/9.93 mg/kg [C-14]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [C-14]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306] ; National Natural Science Foundation of China[81521005]
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000645489200002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296578]
专题	中国科学院上海药物研究所
通讯作者	Zhong, Da-fang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201210, Peoples R China 2.Shanghai Allist Pharmaceut Inc, Shanghai 201203, Peoples R China 3.Soochow Univ, Affiliated Hosp 1, Suzhou 215006, Peoples R China
推荐引用方式 GB/T 7714	Meng, Jian,Zhang, Hua,Bao, Jing-jing,et al. Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans[J]. ACTA PHARMACOLOGICA SINICA,2021:10.
APA	Meng, Jian.,Zhang, Hua.,Bao, Jing-jing.,Chen, Zhen-dong.,Liu, Xiao-yun.,...&Zhong, Da-fang.(2021).Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans.ACTA PHARMACOLOGICA SINICA,10.
MLA	Meng, Jian,et al."Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans".ACTA PHARMACOLOGICA SINICA (2021):10.