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

作　　者：Ze-yu Wang Yong-mei Ren Shu-wei Hu Nai-xia Zhang Meng-xiao Dong Yun Li Yang Yang Zi-jia Guo Shan-sen Xu Jia Chen Aik Han Goh Xiao-yan Chen 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]University of Chinese Academy of Sciences,Beijing,100049,China [3]State Key Laboratory of Chemical Biology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [4]State Key Laboratory of Neurology and Oncology Drug Development,Nanjing,210042,China [5]Simcere Zaiming Pharmaceutical Co.Ltd.,Nanjing,210042,China [6]Jiangsu Simcere Pharmaceutical Co.,Ltd,Nanjing,210042,China

出　　处：《Acta Pharmacologica Sinica》2025年第2期489-499,共11页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.82073924)and grants from State Key Laboratory of Drug Research.

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^(19)F 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.

关 键 词：COVID-19 simnotrelvir ^(19)F qNMR PHARMACOKINETICS METABOLISM mass balance. 

分 类 号：O62[理学—有机化学]