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.