Carey F, Haworth D, Edmonds A E, Forder R A
Research Department II, ICI Pharmaceuticals Division, Macclesfield, Cheshire, U.K.
J Pharmacol Methods. 1988 Dec;20(4):347-56. doi: 10.1016/0160-5402(88)90058-7.
A model is described for determining the pharmacodynamics of inhibitors of arachidonate metabolism in mice. Bioavailability and selectivity were assessed by ex vivo RIA of TXB2, LTB4, and 12-HETE from ionophore-challenged blood. Inhibition of LTB4 and 12-HETE was measured using a single LTB4 RIA, following extraction and separation of these eicosanoids from plasma. Separation on cyanopropyl mini-columns yielded hexane/ether and methanol fractions, which contained 12-HETE and LTB4, respectively. Analgesic efficacy was measured by inhibition of phenylbenzoquinone-induced abdominal constriction. The NSAIDs, indomethacin ibuprofen, flurbiprofen, and benoxaprofen, were analgesic and selective cyclo-oxygenase inhibitors. BW775C was also analgesic, but inhibited cyclo-oxygenase, 5-lipoxygenase and 12-HETE formation. Other in vitro 5-lipoxygenase inhibitors, NDGA, quercetin, and nafazatrom, were inactive in vivo, although NDGA reduced abdominal constrictions. The results indicate that this model has utility in determining the mechanism/selectivity of action and analgesic potential of 5-lipoxygenase inhibitors.
本文描述了一种用于确定小鼠体内花生四烯酸代谢抑制剂药效学的模型。通过对离子载体刺激的血液中的TXB2、LTB4和12-HETE进行体外放射免疫分析（RIA）来评估生物利用度和选择性。在从血浆中提取和分离这些类二十烷酸后，使用单一的LTB4 RIA测量LTB4和12-HETE的抑制作用。在氰丙基微型柱上进行分离，得到己烷/乙醚和甲醇馏分，分别含有12-HETE和LTB4。通过抑制苯醌诱导的腹部收缩来测量镇痛效果。非甾体抗炎药吲哚美辛、布洛芬、氟比洛芬和贝诺洛芬是具有镇痛作用的选择性环氧化酶抑制剂。BW775C也具有镇痛作用，但能抑制环氧化酶、5-脂氧合酶和12-HETE的形成。其他体外5-脂氧合酶抑制剂，如去甲二氢愈创木酸（NDGA）、槲皮素和萘呋胺酯，在体内无活性，尽管NDGA能减少腹部收缩。结果表明，该模型在确定5-脂氧合酶抑制剂的作用机制/选择性和镇痛潜力方面具有实用性。
