Nakamura H, Motoyoshi S, Ishii K, Seto Y, Shimoda A, Kadokawa T
Nihon Yakurigaku Zasshi. 1987 Jan;89(1):15-24. doi: 10.1254/fpj.89.15.
In order to ascertain the mode of anti-inflammatory action of a topical non-steroidal anti-inflammatory drug, etofenamate which is a diethylene glycol ester of flufenamic acid, the in vitro test for the mechanism of the action were carried out. Etofenamate (3 microM) was hydrolysed to flufenamic acid at a rate of 39.5% and 57.0% of the dose during 30 and 60 min incubation, respectively, when incubated with rat peritoneal macrophages stimulated with starch and bacto peptone in phosphate-buffered saline. PGE2 generation by these cells in MEM medium was dose-relatedly inhibited with etofenamate as well as flufenamic acid at the dosage range of 1 to 30 microM. This suggests that unchanged etofenamate is active, since the highest conversion rate of etofenamate to flufenamic acid was 15% of the dose during the incubation. Etofenamate produced a dose-related inhibition against lipoxygenase prepared from peritoneal polymorphonuclear leucocytes of guinea pigs, and its activity (IC50 = 5.3 X 10(-5) M) was stronger than that of caffeic acid; flufenamic acid was inactive. Inhibitory activity of etofenamate was one-third or less that of flufenamic acid against the hypotonic-hyperthermic lysis of rat erythrocytes and heat-denaturation of bovine serum albumin. From these results, it was suggested that topically applied etofenamate produces its anti-inflammatory action through prostaglandin synthesis inhibition by flufenamic acid produced in the inflammatory tissue and inhibition of prostaglandin synthesis by macrophages and lipoxygenase inhibition by unchanged etofenamate.
为了确定一种局部用非甾体抗炎药依托芬那酯（氟芬那酸的二甘醇酯）的抗炎作用方式，进行了其作用机制的体外试验。当在磷酸盐缓冲盐水中与用淀粉和细菌蛋白胨刺激的大鼠腹膜巨噬细胞一起孵育时，依托芬那酯（3 microM）在30分钟和60分钟孵育期间分别以剂量的39.5%和57.0%的速率水解为氟芬那酸。在MEM培养基中，这些细胞产生的PGE2生成在1至30 microM的剂量范围内与依托芬那酯以及氟芬那酸呈剂量相关地受到抑制。这表明未变化的依托芬那酯具有活性，因为在孵育期间依托芬那酯向氟芬那酸的最高转化率为剂量的15%。依托芬那酯对从豚鼠腹膜多形核白细胞制备的脂氧合酶产生剂量相关的抑制作用，其活性（IC50 = 5.3×10(-5) M）强于咖啡酸；氟芬那酸无活性。依托芬那酯对大鼠红细胞的低渗 - 热裂解和牛血清白蛋白的热变性的抑制活性为氟芬那酸的三分之一或更低。从这些结果表明，局部应用的依托芬那酯通过炎症组织中产生的氟芬那酸抑制前列腺素合成、巨噬细胞抑制前列腺素合成以及未变化的依托芬那酯抑制脂氧合酶来产生其抗炎作用。
