Kim Heejung, Huh Jeongsoon, Jeon Hyunchu, Choi Daekyu, Han Jungoh, Kim Youngmi, Jung Yunjin
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
J Pharm Sci. 2009 Jan;98(1):159-68. doi: 10.1002/jps.21404.
To evaluate N,N'-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) as a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis, the pharmacokinetics and therapeutic activity were investigated after oral administration of 5-ASA-Cys and amelioration of experimental colitis was compared after rectal administration of 5-aminosalicylic acid (5-ASA) and/or cysteine. In addition, the gluthathione (GSH) level in the inflamed colonic tissue was examined after administration of cysteine or 5-ASA-Cys. Oral administration of 5-ASA-Cys delivered much greater amount of 5-ASA to the large intestine and excreted lower amount of 5-ASA via urine than that of free 5-ASA. Oral administration of 5-ASA-Cys ameliorated experimental colitis of rats induced by TNBS, which was more effective than that of sulfasalazine. Although cysteine administered rectally was not significantly effective, intracolonic treatment with both 5-ASA and cysteine showed a synergic effect in alleviating the rat colitis. Furthermore, not only 5-ASA-Cys administered orally but also cysteine administered rectally increased the glutathione level in the inflamed colonic tissue. Taken together, these results suggest that 5-ASA-Cys is a potential colon specific 5-ASA prodrug with dual therapeutic effects on experimental colitis and cysteine modulation of the glutathione level may be relevant to the dual effects of the prodrug.
为了评估N,N'-双(5-氨基水杨酸基)-L-胱氨酸(5-ASA-Cys)作为一种潜在的具有双重治疗作用的结肠特异性5-氨基水杨酸前药在实验性结肠炎中的效果，在口服5-ASA-Cys后研究其药代动力学和治疗活性，并比较直肠给予5-氨基水杨酸(5-ASA)和/或半胱氨酸后实验性结肠炎的改善情况。此外，在给予半胱氨酸或5-ASA-Cys后检测炎症结肠组织中的谷胱甘肽(GSH)水平。口服5-ASA-Cys向大肠输送的5-ASA量比游离5-ASA多，且经尿液排泄的5-ASA量更低。口服5-ASA-Cys可改善TNBS诱导的大鼠实验性结肠炎，其效果比柳氮磺胺吡啶更显著。虽然直肠给予半胱氨酸效果不显著，但结肠内同时给予5-ASA和半胱氨酸在减轻大鼠结肠炎方面显示出协同作用。此外，口服5-ASA-Cys以及直肠给予半胱氨酸均可提高炎症结肠组织中的谷胱甘肽水平。综上所述，这些结果表明5-ASA-Cys是一种潜在的结肠特异性5-ASA前药，对实验性结肠炎具有双重治疗作用，且半胱氨酸对谷胱甘肽水平的调节可能与该前药的双重作用有关。
