Yang Yejin, Kim Wooseong, Kim Dayoon, Jeong Seongkeun, Yoo Jin-Wook, Jung Yunjin
College of Pharmacy, Pusan National University, Busan 609-735, South Korea,
Drug Des Devel Ther. 2018 Dec 28;13:231-242. doi: 10.2147/DDDT.S185257. eCollection 2019.
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.
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.
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.
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.
我们研究了多巴胺和5-羟色胺受体调节剂甲氧氯普胺（MCP）在结肠炎实验模型中是否能缓解结肠炎，以及与5-氨基水杨酸（5-ASA）联合使用时是否具有协同作用。
合成了与5-ASA偶联的MCP（5-[4-氯-2-{2-(二乙氨基)乙基氨基甲酰}-1-甲氧基苯基]偶氮水杨酸，MCP-偶氮-ASA），其中5-ASA用作结肠靶向载体和抗结肠炎药物，并评估了MCP-偶氮-ASA在体外和体内靶向结肠的能力。
我们的结果表明，MCP-偶氮-ASA在盲肠内容物中可裂解为MCP和5-ASA，但在小肠内容物中则不能。口服等摩尔浓度的MCP-偶氮-ASA和柳氮磺胺吡啶（SSZ，临床上广泛使用的5-ASA结肠特异性前药）表明，这两种前药向盲肠递送的5-ASA量相当。口服MCP-偶氮-ASA后，血液中几乎检测不到MCP。在2,4-二硝基苯磺酸水合物（DNBS）诱导的大鼠结肠炎模型中，MCP-偶氮-ASA以剂量依赖性方式减轻了结肠损伤。此外，MCP-偶氮-ASA降低了炎症结肠中炎症介质的浓度。在低等摩尔剂量下，MCP-偶氮-ASA而非SSZ产生了显著的抗结肠炎作用，这表明MCP具有抗结肠炎活性。在高等摩尔剂量下，MCP-偶氮-ASA的抗结肠炎作用与SSZ相当。
因此，我们的结果表明，MCP-偶氮-ASA是MCP的结肠特异性前药。将MCP靶向递送至结肠可改善大鼠DNBS诱导的结肠炎，并且我们未观察到MCP与5-ASA联合递送后的任何协同作用。
