Absorption, distribution, metabolism, and excretion of [14C]SHEN211, a nonpeptidic small-molecule 3CLpro inhibitor, in rats.

SHEN211 is a selective 3-chymotrypsin-like protease inhibitor that can protect against severe acute respiratory syndrome coronavirus 2. It is currently being assessed in clinical trials in China, but few studies have reported its metabolism in preclinical and clinical settings. This study used radioactive isotope labeling to investigate the absorption, distribution, metabolism, and excretion of SHEN211 in rats. After a single intragastric administration of 2.0 mg/kg (100 μCi/kg) of [¹⁴C]SHEN211 in rats, the inhibitor was rapidly absorbed, with feces being the primary route of excretion. The results of tissue distribution indicated that SHEN211-related components were mainly concentrated in the liver. In total, 11 metabolites were identified in rat plasma, urine, feces, and bile, and SHEN211 was the major drug-related component in the systemic circulation. The main metabolic pathways of SHEN211 were N-dealkylation, oxidative defluorination, glucuronidation, and glutathione conjugation. In addition, a physiologically based pharmacokinetic model for rats was constructed and validated using GastroPlus software, and the model was extrapolated to healthy adult males to predict the pharmacokinetic characteristics of SHEN211 in humans, providing invaluable insights into the human mass balance of SHEN211 and paving the way for clinical studies. SIGNIFICANCE STATEMENT: This study characterized the absorption, distribution, metabolism, and excretion of SHEN211, a 3CL^pro inhibitor for severe acute respiratory syndrome coronavirus 2 in rats. SHEN211 exhibited rapid absorption and was mainly distributed in the liver. Fecal excretion was the primary elimination route. The prediction of human pharmacokinetic characteristics using the physiologically based pharmacokinetic model provides an invaluable reference for optimizing the clinical dosing strategy of SHEN211 and advancing its ongoing clinical trials in China.