Savidge R D, Bui K H, Birmingham B K, Morse J L, Spreen R C
Drug Disposition and Metabolism Department, Zeneca Pharmaceuticals Group, Wilmington, DE 19897, USA.
Drug Metab Dispos. 1998 Nov;26(11):1069-76.
The in vivo metabolism and excretion of zafirlukast [Accolate; 4, 5-cyclopentoxycarbonylamino-3-[(2-methoxy-4,2- methylphenylsulfonylaminocarbonyl)phenylmethyl]-1-methylindole], a selective peptide leukotriene receptor agonist, were investigated in mice, rats, and dogs. Leukotrienes are a class of compounds that have been identified as being responsible for the contraction of human airway and lung vascular smooth muscle. A chemical agent that is effective in blocking the induced constricting actions of leukotrienes could be used to treat inflammatory processes in the pulmonary system. Zafirlukast has been shown to be clinically efficacious and has been approved for the treatment of asthma in humans. To determine the metabolic fate of zafirlukast, the radiolabeled compound was administered orally to mice, rats, and dogs and iv to rats and dogs. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. Nearly all of the [14C]zafirlukast-derived radioactivity was excreted in the feces of the test species, indicating biliary clearance as the major route of elimination from the systemic circulation. The primary routes of metabolism in all species studied involved hydrolysis of the amide linkage at the 5-aminoindole position and hydroxylation at one or more sites. Additional metabolites were formed by N-acetylation (not in dogs), demethylation of the indole nitrogen, and N-desmethylation. Accolate is a registered trademark, property of Zeneca Ltd.
扎鲁司特[Accolate；4,5-环戊氧基羰基氨基-3-[(2-甲氧基-4,2-甲基苯基磺酰氨基羰基)苯基甲基]-1-甲基吲哚]是一种选择性肽白三烯受体激动剂，研究了其在小鼠、大鼠和犬体内的代谢及排泄情况。白三烯是一类已被确定可导致人气道和肺血管平滑肌收缩的化合物。一种能有效阻断白三烯诱导的收缩作用的化学药剂可用于治疗肺部系统的炎症过程。扎鲁司特已被证明具有临床疗效，并已被批准用于治疗人类哮喘。为确定扎鲁司特的代谢命运，将放射性标记化合物经口给予小鼠、大鼠和犬，经静脉给予大鼠和犬。收集血浆、尿液和粪便样本，测定放射性，并分析代谢产物。几乎所有源自[14C]扎鲁司特的放射性都从受试动物的粪便中排出，表明胆汁清除是从体循环中消除的主要途径。在所有研究的物种中，主要的代谢途径包括5-氨基吲哚位置的酰胺键水解和一个或多个位点的羟基化。还通过N-乙酰化（犬体内未发生）、吲哚氮的去甲基化和N-去甲基化形成了其他代谢产物。Accolate是Zeneca Ltd.的注册商标。
