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19 F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans.
- Source :
-
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2025 Feb; Vol. 46 (2), pp. 489-499. Date of Electronic Publication: 2024 Sep 30. - Publication Year :
- 2025
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Abstract
- 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 <superscript>19</superscript> 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.<br />Competing Interests: Competing interests: YY and JC are employees of Simcere Zaiming Pharmaceutical Co. Ltd. ZJG, SSX, and AHG are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. The other authors declare that they have no competing interests.<br /> (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
- Subjects :
- Humans
Male
Adult
SARS-CoV-2 drug effects
Coronavirus 3C Proteases metabolism
Coronavirus 3C Proteases antagonists & inhibitors
Young Adult
Cytochrome P-450 CYP3A metabolism
Magnetic Resonance Spectroscopy methods
Antiviral Agents pharmacokinetics
COVID-19 Drug Treatment
Tandem Mass Spectrometry methods
Administration, Oral
Organic Chemicals
Ritonavir pharmacokinetics
Feces chemistry
Protease Inhibitors pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1745-7254
- Volume :
- 46
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Acta pharmacologica Sinica
- Publication Type :
- Academic Journal
- Accession number :
- 39349765
- Full Text :
- https://doi.org/10.1038/s41401-024-01393-7