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Although absorption, distribution, metabolism and excretion characteristics of semaglutide have been thoroughly studied in both animals and humans, a reliable in\u00a0vitro screening model for evaluating metabolic behavior of semaglutide and other peptides remains an unmet need in drug development. This study established a novel ultrahigh performance liquid chromatography coupled to high\u2010resolution mass spectrometry method to elucidate the species\u2010specific metabolic pathways of semaglutide. Semaglutide was incubated with liver S9 fractions from human, monkey, dog, rat, and mouse for 1\u2009h, respectively. For the in\u00a0vivo study, rats were subcutaneously injected with semaglutide (10\u2009mg\/kg) for subsequent plasma collection. Data\u2010dependent acquisition was performed to obtain the fragment ions, enabling identification of drug\u2010related materials. Notably, a diagnostic fragment ion at\n                    <jats:italic>m<\/jats:italic>\n                    \/\n                    <jats:italic>z<\/jats:italic>\n                    469, formed from the cleavage of side chain, facilitated metabolite screening. Consequently, a total of 31 metabolites were detected and characterized, constituting a comprehensive metabolic profile of semaglutide in liver S9 fractions and rat plasma. Major metabolic pathways involved hydrolysis of peptide backbone. Our findings provided a robust methodological framework for the screening and metabolism prediction of peptide candidates, supporting the comprehensive safety and efficacy assessment.\n                  <\/jats:p>","DOI":"10.1002\/bmc.70415","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:29:05Z","timestamp":1773030545000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolite Profiling and Identification of Semaglutide in Liver S9 Across Species and Rat Plasma"],"prefix":"10.1002","volume":"40","author":[{"given":"Yawen","family":"Cong","sequence":"first","affiliation":[{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"},{"name":"XenoFinder Co. Ltd.  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