A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model.

Abstract

BACKGROUND:

We examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis.

METHODS:

MCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}- 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated.

RESULTS:

Our results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses.

CONCLUSION:

Thus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.

• Authors: Yejin Yang, Wooseong Kim, Dayoon Kim, Seongkeun Jeong, Jin-Wook Yoo, Yunjin Jung
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 13 Pg. 231-242 ( 2019) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 30643389 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Azo Compounds
• Benzenesulfonates
• Prodrugs
• 2,4-dinitrobenzenesulfonic acid
• Mesalamine
• Metoclopramide

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, chemical synthesis, therapeutic use)
• Azo Compounds (administration & dosage, therapeutic use)
• Benzenesulfonates
• Colitis (chemically induced, drug therapy, pathology)
• Colon (drug effects, pathology)
• Disease Models, Animal
• Male
• Mesalamine (administration & dosage, therapeutic use)
• Metoclopramide (administration & dosage, chemical synthesis, therapeutic use)
• Prodrugs (administration & dosage, chemical synthesis, therapeutic use)
• Rats
• Rats, Sprague-Dawley