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19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans

文献类型：期刊论文

作者Wang, Ze-yu5,6; Ren, Yong-mei6; Hu, Shu-wei4; Zhang, Nai-xia4,5; Dong, Meng-xiao6; Li, Yun6; Yang, Yang2,3; Guo, Zi-jia1,3; Xu, Shan-sen1,3; Chen, Jia2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-09-30
页码11
关键词COVID-19 simnotrelvir F-19 qNMR pharmacokinetics metabolism mass balance.
ISSN号1671-4083
DOI10.1038/s41401-024-01393-7
通讯作者Chen, Xiao-yan(xychen@simm.ac.cn)
英文摘要Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using 19F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma. Of the administered dose, 55.4% (54.3% of M0) was recovered in urine, while 36.7% (4.57% of M0) was excreted in feces. UPLC/Q-TOF MS was used to identify metabolites in human plasma, urine and feces. Notably, oxidative metabolites catalyzed by CYP3A were scarcely detected in these matrixes. The amide hydrolyzed metabolite M9 and the cyano hydrolyzed metabolite M10 were recognized as the predominant metabolites, with the main excretion being through feces (19.0% and 12.7% of the administered dose, respectively). In vitro experiments indicated that M10 is primarily formed in the duodenum and jejunum, with further metabolism to M9 by microbiota in the large intestine. Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota.
资助项目National Natural Science Foundation of China[82073924] ; State Key Laboratory of Drug Research ; First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001325456200002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/313660]  
专题新药研究国家重点实验室
通讯作者Chen, Xiao-yan
作者单位1.Jiangsu Simcere Pharmaceut Co Ltd, Nanjing 210042, Peoples R China
2.Simcere Zaiming Pharmaceut Co Ltd, Nanjing 210042, Peoples R China
3.State Key Lab Neurol & Oncol Drug Dev, Nanjing 210042, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Ze-yu,Ren, Yong-mei,Hu, Shu-wei,et al. 19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans[J]. ACTA PHARMACOLOGICA SINICA,2024:11.
APA Wang, Ze-yu.,Ren, Yong-mei.,Hu, Shu-wei.,Zhang, Nai-xia.,Dong, Meng-xiao.,...&Chen, Xiao-yan.(2024).19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans.ACTA PHARMACOLOGICA SINICA,11.
MLA Wang, Ze-yu,et al."19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans".ACTA PHARMACOLOGICA SINICA (2024):11.

入库方式： OAI收割

来源：上海药物研究所

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