Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans
文献类型：期刊论文
| 作者 | Meng, Jian2 ; Zhang, Hua3; Bao, Jing-jing1; Chen, Zhen-dong2; Liu, Xiao-yun2; Zhang, Yi-fan2; Jiang, Yong1; Miao, Li-yan3; Zhong, Da-fang2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 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 |
| WOS记录号 | WOS:000645489200002 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296578]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhong, Da-fang |
| 作者单位 | 1.Shanghai Allist Pharmaceut Inc, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201210, 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. |
入库方式： OAI收割
来源：上海药物研究所
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