{"paper_id":"13a272b8-3425-4990-8941-e9ac6446780a","body_text":"Rectal Nanoparticulate-Hydrogel Delivery of Corticosteroid Altering Enterohepatic Metabolism and Clearance for Improved Drug Disposition | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Rectal Nanoparticulate-Hydrogel Delivery of Corticosteroid Altering Enterohepatic Metabolism and Clearance for Improved Drug Disposition Rui Xue Zhang, Weijia Lu, Xu Yan, Xudong Deng, Runrun Wan, Zhejun Song, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7232328/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Mar, 2026 Read the published version in Drug Delivery and Translational Research → Version 1 posted 5 You are reading this latest preprint version Abstract Precise dosing is a critical aspect of determining effective therapeutics, but high enterohepatic metabolism poses a significant barrier to many administered small-molecule therapeutics. Orally given budesonide is a potent corticosteroid for treatment of enterohepatic inflammation; yet it undergoes first-pass metabolism by cytochrome P450 3A enzyme abundantly expressed in the liver and intestine, resulting in variable efficacy and unpredictable toxicity. Drug delivery via the rectum is a useful alternative route that can potentially reduce first-pass metabolism. Accordingly, this study investigated whether rectal nanoparticles-hydrogel alter the drug disposition. Budesonide was encapsulated into nanostructured lipid carrier (BD-LNP) for sustained drug release, and then dynamic boronate ester crosslinking hydrogel was prepared to entrap BD-LNP (BD-LNP@Hydrogel) for rectal administration in healthy mice. Compared to BD-LNP, BD-LNP@Hydrogel exhibited 4.3-fold higher nanoparticle exposure to colon lumen, leading to enhanced intestinal uptake of nanoparticles into mucosal deep layer (e.g., lamina propria) in a time-dependent manner. Pharmacokinetic analysis of mouse plasma, liver and intestine showed that rectal BD-LNP@Hydrogel markedly reduced budesonide metabolite formation (16α-hydroxyprednisolone) compared to the oral route. A physiologically-based pharmacokinetic model revealed preferential enterohepatic clearance of budesonide delivered by rectal BD-LNP@Hydrogel to oral route: up to 7.3-fold enhancement in absorption rate constant, dominant intestinal influx transporter clearance, and markedly reduced hepatobiliary and intestinal clearance of metabolite 16α-hydroxyprednisolone in terms of efflux transport and secretion as well as intrinsic clearance for metabolite formation. These findings highlight nanoparticles-hydrogel via the rectum for effective dosing drugs with extensive metabolism and shed light on the physiological mechanistic of rectal delivery. Gastrointestinal-Based Drug Delivery Budesonide Metabolite First-Pass Metabolism Pharmacokinetics PKPB Model Full Text Supplementary Files Suppl.Mater.0728final.docx Cite Share Download PDF Status: Published Journal Publication published 20 Mar, 2026 Read the published version in Drug Delivery and Translational Research → Version 1 posted Editorial decision: Major Revisions Needed 29 Sep, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers invited by journal 20 Aug, 2025 Editor assigned by journal 01 Aug, 2025 First submitted to journal 28 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7232328\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":503008556,\"identity\":\"aef013a5-d83d-4a19-a723-0a0884508521\",\"order_by\":0,\"name\":\"Rui Xue Zhang\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYDACCQjFA8SMD6BiBkRrYTaA8onTAgJsEkRpkZ/d/Ozh1z2HZQxuJB+rutlWV8fA3rxNgjHHBqcWxjnHzI1lnh3mkZyRlnY7t+2wBAPPsTIJxm1pOLUwSySYSUscOMzDL5FjBtRyQIIByABqOYxTC5tE+jewFjaJ/G/FuW11Egzyb/Br4QGaKfkBYgsbc24bM9AWHvxaJCRyyqQZDqTzSPY8M5bOOXdYso0nrdgiEY9f5Gekb5P8ccDa3uB48sPPOWV1/Pzshzfe+LgNd4iBg4AHxXcgIgGvBmBA/yCgYBSMglEwCkY4AADLjUm+ajbgIwAAAABJRU5ErkJggg==\",\"orcid\":\"https://orcid.org/0000-0002-9418-8125\",\"institution\":\"Macau University of Science and Technology Medical Sciences Division\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Rui\",\"middleName\":\"Xue\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":503008557,\"identity\":\"3097ddca-1cb7-4a7b-8145-142f3ad52f65\",\"order_by\":1,\"name\":\"Weijia Lu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Weijia\",\"middleName\":\"\",\"lastName\":\"Lu\",\"suffix\":\"\"},{\"id\":503008558,\"identity\":\"188dcf5d-61db-4dd5-b24b-358dcc0b05b9\",\"order_by\":2,\"name\":\"Xu Yan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xu\",\"middleName\":\"\",\"lastName\":\"Yan\",\"suffix\":\"\"},{\"id\":503008559,\"identity\":\"9be02c6b-2278-47c4-96c2-8d8568acdc13\",\"order_by\":3,\"name\":\"Xudong Deng\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xudong\",\"middleName\":\"\",\"lastName\":\"Deng\",\"suffix\":\"\"},{\"id\":503008560,\"identity\":\"fe0d876d-62a0-4585-81c4-a49c850dcf32\",\"order_by\":4,\"name\":\"Runrun Wan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Runrun\",\"middleName\":\"\",\"lastName\":\"Wan\",\"suffix\":\"\"},{\"id\":503008561,\"identity\":\"3c452734-6195-45a0-94c6-13423282e7a6\",\"order_by\":5,\"name\":\"Zhejun Song\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Macau University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhejun\",\"middleName\":\"\",\"lastName\":\"Song\",\"suffix\":\"\"},{\"id\":503008562,\"identity\":\"eb9e40a9-7b10-418e-af16-e350b9dfe654\",\"order_by\":6,\"name\":\"Tingting Cao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tingting\",\"middleName\":\"\",\"lastName\":\"Cao\",\"suffix\":\"\"},{\"id\":503008563,\"identity\":\"3219d693-442f-4dc5-a5c4-8962ec6e89e9\",\"order_by\":7,\"name\":\"Xue-Ting Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Northwestern Polytechnical University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xue-Ting\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":503008564,\"identity\":\"fbe6fddd-bf07-47a8-9d6d-4938ba2a157e\",\"order_by\":8,\"name\":\"Yan Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Macau University of Science and Technology Medical Sciences Division\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yan\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":503008565,\"identity\":\"de21f7ef-eb33-47f7-96f2-87616c245a7a\",\"order_by\":9,\"name\":\"Paul K.H. 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