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.

Keywords:

• metoclopramide
• 5-aminosalicylic acid
• colon-specific prodrug
• colitis
• serotonin
• dopamine

Acknowledgments

This research was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2018R1D1A3B07045694).

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

Figure S1 IR (A) and ¹H-NMR (B) spectra of 5-aminosalicylic acid (5-ASA), metoclopramide (MCP), and metoclopramide azo-linked to 5-aminoslicylic acid (MCP-azo-ASA).

Abbreviations: IR, infrared; ¹H-NMR, proton nuclear magnetic resonance.

Figure S2 Photos of the luminal and serosal sides of distal colons.

Notes: Metoclopramide (MCP, 22.4 mg/kg, equimolar to 33.8 mg/kg MCP-azo-ASA) was administered to rats with 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis by oral gavage once a day, and the rats were euthanized 7 days after treatment with the drug. The luminal and serosal sides of distal colons were photographed.
Abbreviation: MCP-azo-ASA, metoclopramide azo-linked to 5-aminosalicylic acid.