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KMID : 1146920210510030317
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Journal of Pharmaceutical Investigation
2021 Volume.51 No. 3 p.317 ~ p.325
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5-[(3-Carboxy-4-hydroxyphenyl)diazenyl] nicotinic acid, an azo-linked mesalazine-nicotinic acid conjugate, is a colon-targeted mutual prodrug against dextran sulfate sodium-induced colitis in mice
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Jeong Seong-Keun
Ju Sang-Hyun
Park So-Hee
Jung Yun-Jin
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Abstract
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Purpose: We aimed to develop a 5-aminosalicylic acid (5-ASA, mesalazine)-based anti-colitic drug with higher efficacy than sulfasalazine (SSZ), a colon-targeted prodrug of 5-ASA, for the treatment of inflammatory bowel disease (IBD). To this end, we synthesized a colon-targeted mutual prodrug (ASA-azo-NA) consisting of 5-ASA and the GPR109A agonist nicotinic acid, 5-[(3-carboxy-4-hydroxyphenyl)diazenyl] nicotinic acid.
Methods: In our previous study, oral gavage of ASA-azo-NA delivered 5-ASA and 5-aminonicotinic acid specifically to the large intestine in a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model and ameliorated colonic damage and inflammation more effectively than oral SSZ. To increase the therapeutic convincibility of ASA-azo-NA for the treatment of IBD with multifactorial pathologies, the colon targetability and therapeutic activity of ASA-azo-NA were examined using a dextran sulfate sodium (DSS)-induced colitis mouse model with a different pathogenesis from that of DNBS-induced colitis in rats.
Results: ASA-azo-NA liberated 5-ASA in the cecal contents of mice while remaining stable in the small intestinal contents, with a cecal conversion rate and extent comparable to those of SSZ. Oral ASA-azo-NA and SSZ accumulated similar concentrations of 5-ASA in the cecum, indicating that ASA-azo-NA was delivered to and activated in the large intestine as efficiently as SSZ. In mice with DSS-induced colitis, oral ASA-azo-NA mitigated colonic damage and inflammation, as assessed using macroscopic and molecular indices, and was therapeutically superior to SSZ.
Conclusion: ASA-azo-NA acted as a colon-targeted mutual prodrug against DSS-induced mouse colitis. Thus, ASA-azo-NA may be therapeutically applicable to patients with IBD who are resistant to SSZ treatment.
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KEYWORD
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5-Aminosalicylic acid, Nicotinic acid, GPR109A, Colon-targeted drug delivery, Mutual prodrug, Inflammatory bowel disease, DSS-induced mouse colitis
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