{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:16:15Z","timestamp":1753892175362,"version":"3.41.2"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Deglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A combination of UPLC-QTOF-MS was used to obtain metabolite spectra of Deg-AZM in plasma, urine, feces and bile. Caco-2 cells was used to investigate the permeability of Deg-AZM and whether it is a potential substrate of the efflux transporter P-glycoprotein. Human liver microsome phenotyping assays with chemical inhibition and recombinant CYPs phenotyping assays were used to investigate the CYP450 enzyme phenotype involved in Deg-AZM metabolism <jats:italic>in vitro<\/jats:italic>. A HLM inhibition reaction system was established to evaluate the inhibitory effect of Deg-AZM on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The mRNA expression of human primary hepatocytes incubated with Deg-AZM or not was evaluate the induction of Deg-AZM on CYP1A2, CYP2B6, and CYP3A4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>44 metabolites of Deg-AZM were identified in rat urine, feces, bile, and plasma, the metabolic pathways included demethylation, monohydroxylation, dihydroxylation, dehydroxidation, hydroreduction, hydrolysis, methylation, glucuronidation and the combination of different metabolic pathways. Deg-AZM was a low permeability drug in the intestine and a potential substrate of the efflux transporter P-glycoprotein. CYP3A4 was the major CYP isoform responsible for Deg-AZM metabolism. Deg-AZM showed moderate inhibition with CYP2B6 and CYP2D6. Data in three batches of human primary hepatocytes disclosed induction potential of Deg-AZM on CYP2B6 and CYP3A4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>in vivo<\/jats:italic> metabolic pathway of Deg-AZM and <jats:italic>in vitro<\/jats:italic> possibility of drug interaction for Deg-AZM with CYP enzymes and drug transporter were fully investigated. It was suggested that dose adjustments may be warranted depending on the potency of the corresponding modulators in clinical.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1510903","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T05:12:36Z","timestamp":1736313156000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The in vivo metabolic pathway of Deg-AZM and in vitro investigations into the contribution of drug metabolizing enzymes and drug transporters in the drug interactions of Deg-AZM, a clinical-stage new transgelin agonist"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaoting","family":"Gu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohe","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixue","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoyue","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutian","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conglu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhilin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuwen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honggang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Ai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1111\/jcpt.12721","article-title":"Efficacy and safety of laxatives for chronic constipation in long-term care settings: a systematic review","volume":"43","author":"Alsalimy","year":"2018","journal-title":"J. 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