A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Drug design, development and therapy - 13(2019) vom: 07., Seite 231-242 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Yejin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.05.2019 Date Revised 31.03.2022 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.2147/DDDT.S185257 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM292714823 |
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| 100 | 1 | |a Yang, Yejin |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 29.05.2019 | ||
| 500 | |a Date Revised 31.03.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 5-aminosalicylic acid | |
| 650 | 4 | |a colitis | |
| 650 | 4 | |a colon-specific prodrug | |
| 650 | 4 | |a dopamine | |
| 650 | 4 | |a metoclopramide | |
| 650 | 4 | |a serotonin | |
| 650 | 7 | |a Anti-Inflammatory Agents, Non-Steroidal |2 NLM | |
| 650 | 7 | |a Azo Compounds |2 NLM | |
| 650 | 7 | |a Benzenesulfonates |2 NLM | |
| 650 | 7 | |a Prodrugs |2 NLM | |
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| 650 | 7 | |a Mesalamine |2 NLM | |
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| 700 | 1 | |a Kim, Wooseong |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Dayoon |e verfasserin |4 aut | |
| 700 | 1 | |a Jeong, Seongkeun |e verfasserin |4 aut | |
| 700 | 1 | |a Yoo, Jin-Wook |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Yunjin |e verfasserin |4 aut | |
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