Carter G W, Young P R, Albert D H, Bouska J, Dyer R, Bell R L, Summers J B, Brooks D W
Immunosciences Research Area, Abbott Laboratories, Illinois.
J Pharmacol Exp Ther. 1991 Mar;256(3):929-37.
Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.
齐留通[N-(1-苯并[b]噻吩-2-基乙基)-N-羟基脲]分别抑制大鼠嗜碱性白血病细胞20,000×g上清液和大鼠多形核白细胞(PMNL)合成5-羟基二十碳四烯酸(IC50 = 0.5和0.3微摩尔)。它还抑制大鼠PMNL(IC50 = 0.4微摩尔)、人PMNL(IC50 = 0.4微摩尔)和人全血(IC50 = 0.9微摩尔)合成白三烯(LT)B4。通过简单的洗涤程序可轻易消除对人PMNL LTB4生物合成的抑制。在浓度高达100微摩尔时，该化合物对几种相关酶几乎没有或没有抑制作用，如血小板12-脂氧合酶、大豆和兔网织红细胞15-脂氧合酶以及绵羊精囊环氧化酶。在犬中口服剂量为0.5至5毫克/千克时，齐留通可快速且持续地抑制离体血液LTB4生物合成，这与该化合物的药代动力学行为相关。在大鼠的类似离体研究中，该化合物的口服ED50为2毫克/千克。齐留通在预防由抗原-抗体反应引发的大鼠腹腔内6-硫代肽白三烯形成方面非常有效，ED50为3毫克/千克。在炎症实验模型中，齐留通显著减轻花生四烯酸诱导的小鼠耳部水肿(ED50 = 31毫克/千克)，并减轻大鼠胸膜Arthus反应中的炎症细胞聚集。该化合物在体外、离体和体内预防白三烯形成的有效性表明其可用于预防白三烯和其他5-脂氧合酶产物在动物和人类中的病理生理作用。
