Husain Asif, Ahuja Priyanka, Ahmad Aftab, Khan Shah A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi-110062, India.
Med Chem. 2016;12(6):585-91. doi: 10.2174/1573406412666160107113548.
Non steroidal anti-inflammatory drugs are the most widely prescribed drugs to manage pain and inflammatory conditions, but their long term use is associated with gastrointestinal toxicity.
The study aimed to synthesize an ester-based prodrug of a non steroidal anti-inflammatory agent, mefenamic acid in order to improve the therapeutic index vis a vis to overcome the side effects such as gastrointestinal irritation and bleeding associated with the use of mefenamic acid.
The ester prodrug (MA-NH) was prepared by condensing mefenamic acid with N-hydroxymethylsuccinimide in the presence of Phosphorus oxychloride. The pharmacokinetic profile, including stability and release of mefenamic acid and N-hydroxymethylsuccinimide from the ester prodrug (MA-NH) was studied by RP- HPLC in acidic medium (pH 1.2), basic medium (pH 7.4), 80 % v/v human plasma, 10 % w/v rat intestinal homogenate and 10 % w/v rat liver homogenate (pH 7.4).
The chemical structure of the title compound was characterized by using modern spectroscopic techniques. The prodrug was found to be stable in acid medium, but it hydrolyzed and released sufficient quantities of the drug in alkaline medium. The prodrug produced lesser number of ulcers and showed improved analgesic and anti-inflammatory activity as compared to the parent drug.
The results indicate that the synthesized prodrug (MA-NH) is better in terms of analgesic and antiinflammatory activities and with less GI toxicity than the parent drug.
非甾体抗炎药是治疗疼痛和炎症性疾病最常用的药物，但其长期使用会导致胃肠道毒性。
本研究旨在合成一种基于酯的非甾体抗炎药甲芬那酸前药，以提高治疗指数，克服与使用甲芬那酸相关的胃肠道刺激和出血等副作用。
在三氯氧磷存在下，将甲芬那酸与N-羟甲基琥珀酰亚胺缩合制备酯前药（MA-NH）。通过反相高效液相色谱法在酸性介质（pH 1.2）、碱性介质（pH 7.4）、80% v/v人血浆、10% w/v大鼠肠匀浆和10% w/v大鼠肝匀浆（pH 7.4）中研究了酯前药（MA-NH）中甲芬那酸和N-羟甲基琥珀酰亚胺的药代动力学特征，包括稳定性和释放情况。
采用现代光谱技术对标题化合物的化学结构进行了表征。发现前药在酸性介质中稳定，但在碱性介质中水解并释放出足够量的药物。与母体药物相比，前药产生的溃疡数量较少，镇痛和抗炎活性有所提高。
结果表明，合成的前药（MA-NH）在镇痛和抗炎活性方面优于母体药物，且胃肠道毒性较小。
