{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:19:08Z","timestamp":1763975948303,"version":"3.45.0"},"reference-count":48,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2021R1I1A3A0403710411"],"award-info":[{"award-number":["2021R1I1A3A0403710411"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. Methods: CAA exhibited reduced lipophilicity and decreased transintestinal transport compared to CBT, as shown in an ex vivo experiment using isolated rat jejunal segments. It also underwent cleavage into CBT and 5-ASA when incubated with cecal contents of rats. Additionally, oral administration of CAA and Sulfasalazine (SSZ), a colon-specific prodrug of 5-ASA currently used for IBD treatment, resulted in similar levels of 5-ASA accumulation in the rat cecal region. Results: In a dinitrobenzene sulfonic acid-triggered colitis model in rats, CAA produced a more pronounced improvement in colon injury and inflammation than SSZ. Furthermore, rectal co-administration of CBT and 5-ASA conferred enhanced protective outcomes compared to monotherapy with either agent alone, suggesting a combined anticolitic action. The two drugs also jointly suppressed valacyclovir uptake via peptide transporter 1 (PepT1) in the distal colon, supporting PepT1 as a target contributing to their combined anticolitic effect. Unlike CBT, which significantly reduced blood glucose following oral administration, equimolar administration of CAA did not alter glycemic levels, consistent with reduced systemic exposure to CBT. Conclusions: In conclusion, CAA functions as a colon-specific mutual prodrug that surpasses SSZ in anticolitic performance while minimizing hypoglycemia risk, thus facilitating the repurposing of CBT as a treatment for IBD.<\/jats:p>","DOI":"10.3390\/pharmaceutics17121509","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:02:07Z","timestamp":1763974927000},"page":"1509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Carbutamide, an Obsolete Anti-Diabetic Drug, Has Potential as a Potent Anticolitic Agent via Azo-Conjugation with Mesalazine"],"prefix":"10.3390","volume":"17","author":[{"given":"Sanghyun","family":"Ju","sequence":"first","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suji","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taeyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5216-5518","authenticated-orcid":false,"given":"Jin-Wook","family":"Yoo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0997-5723","authenticated-orcid":false,"given":"In-Soo","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-8280","authenticated-orcid":false,"given":"Eunsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjin","family":"Jung","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.2174\/13816128113199990416","article-title":"Inflammatory bowel disease: Etiology, pathogenesis and current therapy","volume":"20","author":"Ko","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nature06005","article-title":"Unravelling the pathogenesis of inflammatory bowel disease","volume":"448","author":"Xavier","year":"2007","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.trsl.2016.04.009","article-title":"Inflammatory bowel disease: Exploring gut pathophysiology for novel therapeutic targets","volume":"176","author":"Yadav","year":"2016","journal-title":"Transl. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"90","DOI":"10.3109\/00365521.2014.968864","article-title":"Conventional drug therapy for inflammatory bowel disease","volume":"50","author":"Bryant","year":"2015","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S1734-1140(11)70575-8","article-title":"Treatment of inflammatory bowel disease (IBD)","volume":"63","author":"Pithadia","year":"2011","journal-title":"Pharmacol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/13543784.2022.2032639","article-title":"JAK inhibitors in crohn\u2019s disease: Ready to go?","volume":"31","author":"Gabbiadini","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4110\/in.2017.17.1.25","article-title":"Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies","volume":"17","author":"Kim","year":"2017","journal-title":"Immune Netw."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e101023222023","DOI":"10.2174\/0115701638253929230922115127","article-title":"Drug Repositioning: A Monetary Stratagem to Discover a New Application of Drugs","volume":"21","author":"Rohilla","year":"2024","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/17460441.2020.1704729","article-title":"Challenges and opportunities with drug repurposing: Finding strategies to find alternative uses of therapeutics","volume":"15","author":"Talevi","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1021\/acs.molpharmaceut.9b00664","article-title":"Colon-Targeted Delivery Facilitates the Therapeutic Switching of Sofalcone, a Gastroprotective Agent, to an Anticolitic Drug via Nrf2 Activation","volume":"16","author":"Kim","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1021\/acs.molpharmaceut.2c00255","article-title":"A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug","volume":"19","author":"Park","year":"2022","journal-title":"Mol. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1517\/17425240903490401","article-title":"What should be considered on design of a colon-specific prodrug?","volume":"7","author":"Jung","year":"2010","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v24.i2.20","article-title":"Therapeutic opportunities in colon-specific drug-delivery systems","volume":"24","author":"Patel","year":"2007","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1365-2036.2008.03751.x","article-title":"Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis--methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa","volume":"28","author":"Lichtenstein","year":"2008","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1007\/s12272-015-0602-y","article-title":"Colonic delivery of celecoxib is a potential pharmaceutical strategy for repositioning the selective COX-2 inhibitor as an anti-colitic agent","volume":"38","author":"Kim","year":"2015","journal-title":"Arch. Pharm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1080\/14656566.2021.1999413","article-title":"The role of sulfonylureas in the treatment of type 2 diabetes","volume":"23","author":"Tomlinson","year":"2022","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kewcharoenwong, C., Rinchai, D., Utispan, K., Suwannasaen, D., Bancroft, G.J., Ato, M., and Lertmemongkolchai, G. (2013). Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection. Sci. Rep., 3.","DOI":"10.1038\/srep03363"},{"key":"ref_19","first-page":"27","article-title":"Hypoglycemic agents and potential anti-inflammatory activity","volume":"9","author":"Kothari","year":"2016","journal-title":"J. Inflamm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.atherosclerosis.2012.11.016","article-title":"Up-regulated ATP-sensitive potassium channels play a role in increased inflammation and plaque vulnerability in macrophages","volume":"226","author":"Ling","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0022-3565(24)29317-4","article-title":"Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors","volume":"299","author":"Perregaux","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.drudis.2018.08.005","article-title":"Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys","volume":"24","author":"Yaribeygi","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nm.3806","article-title":"A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases","volume":"21","author":"Coll","year":"2015","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1083\/jcb.200903124","article-title":"Glyburide inhibits the Cryopyrin\/Nalp3 inflammasome","volume":"187","author":"Lamkanfi","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1002\/cmdc.201700270","article-title":"Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors","volume":"12","author":"Hill","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1007\/s13300-021-01059-1","article-title":"Sulfonylureas in the Current Practice of Type 2 Diabetes Management: Are They All the Same? Consensus from the Gulf Cooperation Council (GCC) Countries Advisory Board on Sulfonylureas","volume":"12","author":"Sabico","year":"2021","journal-title":"Diabetes Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1136\/bmj.1.5179.1089","article-title":"Carbutamide in diabetes: Report of a long-term trial, with special reference to late failures","volume":"1","author":"Markkanen","year":"1960","journal-title":"Br. Med. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/sj.bjp.0702895","article-title":"Effects of glibenclamide on glycylsarcosine transport by the rat peptide transporters PEPT1 and PEPT2","volume":"128","author":"Sawada","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/labinvest.2013.77","article-title":"PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis","volume":"93","author":"Ayyadurai","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16099","DOI":"10.1074\/jbc.M115.659318","article-title":"MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1","volume":"290","author":"Dai","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1053\/j.gastro.2007.10.026","article-title":"PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation","volume":"134","author":"Dalmasso","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"G888","DOI":"10.1152\/ajpgi.00299.2020","article-title":"PepT1-knockout mice harbor a protective metabolome beneficial for intestinal wound healing","volume":"320","author":"Sung","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1056\/NEJM195701102560207","article-title":"Toxicity of carbutamide; report of a fatal case of bone-marrow depression and anuria","volume":"256","author":"Hare","year":"1957","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2165\/00003495-198600321-00003","article-title":"Sulphasalazine: A review of 40 years\u2019 experience","volume":"32","author":"Watkinson","year":"1986","journal-title":"Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1007\/s10620-008-0481-x","article-title":"A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis","volume":"54","author":"Nikfar","year":"2009","journal-title":"Dig. Dis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"78920","DOI":"10.1039\/C5RA11635J","article-title":"Enhancement of the sensitivity of valacyclovir and acyclovir for their spectrofluorimetric determination in human plasma","volume":"5","author":"Derayea","year":"2015","journal-title":"RSC Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e12835","DOI":"10.1111\/jpi.12835","article-title":"N-Acetylserotonin is an oxidation-responsive activator of Nrf2 ameliorating colitis in rats","volume":"74","author":"Kang","year":"2023","journal-title":"J. Pineal Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1007\/s11095-005-6250-z","article-title":"Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease","volume":"22","author":"Kim","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_39","first-page":"CD000544","article-title":"Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis","volume":"8","author":"Murray","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"G687","DOI":"10.1152\/ajpgi.00527.2009","article-title":"PepT1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-gamma-D-Glu-meso-DAP in intestinal epithelial cells","volume":"299","author":"Dalmasso","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1248\/bpb.b17-00181","article-title":"Inhibitory Potency of Marketed Drugs for Ulcerative Colitis and Crohn\u2019s Disease on PEPT1","volume":"40","author":"Miyake","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1006\/bbrc.1998.8628","article-title":"Valacyclovir: A substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2","volume":"246","author":"Ganapathy","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"G66","DOI":"10.1152\/ajpgi.00491.2012","article-title":"The peptide transporter PEPT1 is expressed in distal colon in rodents and humans and contributes to water absorption","volume":"305","author":"Wuensch","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1517\/17425247.4.5.547","article-title":"Azo compounds in colon-specific drug delivery","volume":"4","author":"Roldo","year":"2007","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"G484","DOI":"10.1152\/ajpgi.00477.2011","article-title":"The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease","volume":"302","author":"Ingersoll","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1002\/eji.200939602","article-title":"Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease","volume":"39","author":"Uhlig","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_47","first-page":"99","article-title":"Azo reductase activity of microbial population from gastrointestinal tract segments of various animals species","volume":"36","author":"Das","year":"1998","journal-title":"Indian J. Exp. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.toxrep.2018.08.017","article-title":"The use of structural alerts to avoid the toxicity of pharmaceuticals","volume":"5","author":"Limban","year":"2018","journal-title":"Toxicol. Rep."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/12\/1509\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:15:13Z","timestamp":1763975713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/12\/1509"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,22]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["pharmaceutics17121509"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17121509","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,22]]}}}