El-Kamel Amal H, Abdel-Aziz Alaa A-M, Fatani Amal J, El-Subbagh Hussein I
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Int J Pharm. 2008 Jun 24;358(1-2):248-55. doi: 10.1016/j.ijpharm.2008.04.021. Epub 2008 Apr 20.
The aim of this study was to investigate the potential of prodrugs of some non-steroidal anti-inflammatory drugs (NSAIDs) as colon targeted delivery systems for treatment of inflammatory bowel diseases. Naproxen, sulindac and flurbiprofen (Fbp) were used. The carboxylic group of those drugs was conjugated onto the amino group of l-aspartic acid or the hydroxyl group of alpha- or beta-cyclodextrin (CyD). Prodrugs hydrolysis in buffers of pH range 1.2-7.2 and in rat gastrointestinal tract homogenates and the effect of oral pretreatment of rats with clindamycin on the hydrolysis of the prodrugs was examined. Additionally, the effect of oral administration of Fbp-beta-CyD prodrug on the experimentally induced colitis in rats was evaluated. The in vivo inflammatory response was assessed macroscopically, histologically and by measurement of reduced glutathione (GSH) levels in colon tissues. No significant hydrolysis of the proposed seven prodrugs in buffers having pH range of 1.2-7.2 was observed over 72h. Negligible % of drug released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs was detected in rat stomach contents, intestinal tissues and intestinal contents homogenates. On the other hand, Fbp-alpha-CyD and Fbp-beta-CyD prodrugs released about 60% Fbp within 4h in rat colon homogenate. Oral pretreatment of rats with clindamycin significantly reduced % Fbp released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs. Oral administration of Fbp-beta-CyD to rats after induction of colitis significantly attenuated the severity of the colonic injury and reduced the score of the macroscopic and microscopic damage. Additionally, there was a significant increase in the level of GSH. The present study provided an evidence that Fbp-beta-CyD prodrug may be beneficial in treatment of inflammatory bowel disease.
本研究的目的是研究某些非甾体抗炎药（NSAIDs）的前体药物作为结肠靶向给药系统治疗炎症性肠病的潜力。使用了萘普生、舒林酸和氟比洛芬（Fbp）。这些药物的羧基与L-天冬氨酸的氨基或α-或β-环糊精（CyD）的羟基共轭。研究了前体药物在pH范围为1.2 - 7.2的缓冲液以及大鼠胃肠道匀浆中的水解情况，以及用克林霉素对大鼠进行口服预处理对前体药物水解的影响。此外，还评估了口服给予Fbp-β-CyD前体药物对大鼠实验性诱导结肠炎的影响。通过宏观、组织学评估以及测量结肠组织中还原型谷胱甘肽（GSH）水平来评估体内炎症反应。在72小时内，未观察到所提出的七种前体药物在pH范围为1.2 - 7.2的缓冲液中有明显水解。在大鼠胃内容物、肠道组织和肠道内容物匀浆中，未检测到从Fbp-α-CyD或Fbp-β-CyD前体药物中释放出的可忽略不计的药物百分比。另一方面，Fbp-α-CyD和Fbp-β-CyD前体药物在大鼠结肠匀浆中4小时内释放了约60%的Fbp。用克林霉素对大鼠进行口服预处理显著降低了从Fbp-α-CyD或Fbp-β-CyD前体药物中释放的Fbp百分比。在诱导结肠炎后给大鼠口服Fbp-β-CyD显著减轻了结肠损伤的严重程度，并降低了宏观和微观损伤的评分。此外，GSH水平有显著升高。本研究提供了证据表明Fbp-β-CyD前体药物可能对炎症性肠病的治疗有益。
