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用于治疗溃疡性结肠炎的5-氨基水杨酸前药的合成与评价

Synthesis and evaluation of a prodrug of 5-aminosalicylic acid for the treatment of ulcerative colitis.

作者信息

Yan Yan, Ren Fengling, Wang Pengchong, Sun Ying, Xing Jianfeng

机构信息

School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

出版信息

Iran J Basic Med Sci. 2019 Dec;22(12):1452-1461. doi: 10.22038/IJBMS.2019.13991.

DOI:10.22038/IJBMS.2019.13991
PMID:32133064
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7043877/
Abstract

OBJECTIVES

This study is aimed to design and synthesize a prodrug of 5-aminosalicylic acid and evaluate its ameliorative effect on experimental ulcerative colitis (UC).

MATERIALS AND METHODS

5-Aminosalicylic acid-alanine (5-ASA-ALA) was synthesized and characterized. Its stability study was conducted in rat plasma and in the gastrointestinal tract environment, its transport characteristic was assessed using the Caco-2 cells. Its colon-targeting property was evaluated by the pharmacokinetic study, and incubation studies. A series of indicators were used to investigate its therapeutic effect on experimental colitis, including the survival rate and body weight of mice, the disease activity index (DAI), the colonic damage score and colon index, the myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), total superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) in colonic tissues.

RESULTS

5-ASA-ALA was barely absorbed in the Caco-2 monolayer or into the rat blood. It was remarkably stable when incubated in the upper gastrointestinal tract, while gradually hydrolyzed in the colon of rats. When orally administered to mice, 5-ASA-ALA had significantly greater therapeutic effect on colitis than the positive control.

CONCLUSION

5-ASA-ALA is demonstrated to be a promising oral colon-targeting prodrug of 5-ASA and has potential application in UC treatment.

摘要

目的

本研究旨在设计并合成5-氨基水杨酸的前体药物，并评估其对实验性溃疡性结肠炎（UC）的改善作用。

材料与方法

合成并表征了5-氨基水杨酸-丙氨酸（5-ASA-ALA）。在大鼠血浆和胃肠道环境中进行其稳定性研究，使用Caco-2细胞评估其转运特性。通过药代动力学研究和孵育研究评估其结肠靶向特性。使用一系列指标研究其对实验性结肠炎的治疗效果，包括小鼠的存活率和体重、疾病活动指数（DAI）、结肠损伤评分和结肠指数、髓过氧化物酶（MPO）活性以及结肠组织中丙二醛（MDA）、总超氧化物歧化酶（SOD）、谷胱甘肽（GSH）和谷胱甘肽过氧化物酶（GSH-Px）的水平。

结果

5-ASA-ALA在Caco-2单层细胞或大鼠血液中几乎不被吸收。在上消化道孵育时它非常稳定，而在大鼠结肠中逐渐水解。当口服给予小鼠时，5-ASA-ALA对结肠炎的治疗效果明显优于阳性对照。

结论

5-ASA-ALA被证明是一种有前景的5-ASA口服结肠靶向前体药物，在UC治疗中具有潜在应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20ec/7043877/e63572a2384f/IJBMS-22-1452-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20ec/7043877/33c09c6f86d5/IJBMS-22-1452-g007.jpg
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