Philip Anil K, Dabas Sunny, Pathak Kamla
Department of Pharmaceutics, Rajiv Academy for Pharmacy, Uttar Pradesh, India.
J Drug Target. 2009 Apr;17(3):235-41. doi: 10.1080/10611860902718656.
In the present study, prodrug of ketoprofen was synthesized and evaluated in vitro to optimize the prodrug, and in vivo to observe the reduction in gastrointestinal disturbance and enhanced colonic anti- inflammatory potential for the prodrug. The prodrug was synthesized by coupling ketoprofen with L-glycine (KET-GLY). In vitro reversion of KET-GLY to ketoprofen was carried out in different pHs and in pH 6.8 containing optimized rat fecal material. In vivo healing potential of KET-GLY was evaluated in acetic acid-induced experimental colitis model. In vitro reversion studies suggested that KET-GLY remained intact in stomach but released the free drug at pH 6.8 containing fresh rat fecal material, where the colonic microfloral enzymes (amidase) hydrolyzed the KET-GLY amide linkage, releasing the free drug. In vivo evaluation indicated KET-GLY to be less toxic in stomach, with enhanced anti-inflammatory potential in the colonic region. These findings suggested KET-GLY to be better in action compared with the parent drug.
在本研究中，合成了酮洛芬前药并进行体外评估以优化该前药，同时进行体内评估以观察前药对胃肠道紊乱的减轻作用以及增强的结肠抗炎潜力。该前药通过将酮洛芬与L-甘氨酸偶联（KET-GLY）合成。在不同pH值以及含有优化的大鼠粪便物质的pH 6.8条件下进行KET-GLY向酮洛芬的体外转化。在乙酸诱导的实验性结肠炎模型中评估KET-GLY的体内愈合潜力。体外转化研究表明，KET-GLY在胃中保持完整，但在含有新鲜大鼠粪便物质的pH 6.8条件下释放游离药物，在此处结肠微生物酶（酰胺酶）水解KET-GLY的酰胺键，释放出游离药物。体内评估表明，KET-GLY在胃中的毒性较小，在结肠区域具有增强的抗炎潜力。这些发现表明，与母体药物相比，KET-GLY的作用更好。
