Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.
Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.
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孟鲁司特钠（顺尔宁）是一种有效的半胱氨酰白三烯 1 受体拮抗剂，在人血浆和胆汁中的代谢特征。
DOI：
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发表时间：
1997
影响因子：
3.9
通讯作者：
T. Baillie
中科院分区：
文献类型：
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作者：
S. Balani;X. Xu;V. Pratha;M. Koss;R. Amin;Claude Dufresne;R. Miller;B. Arison;George A. Doss;M. Chiba;A. Freeman;S. Holland;J. Schwartz;K. Lasseter;B. Gertz;Jon I. Isenberg;J. Rogers;J. Lin;T. Baillie
孟鲁司特钠[1-([(1（R)-（3-（2-（7-氯-2-喹啉基）-（E)-乙烯基）苯基）-3-（2-（1-羟基-1-甲基乙基）苯基）丙基）硫]甲基）环丙基乙酸钠盐]（MK-476, Singulair）是半胱氨酸白三烯（Cys-LT1）受体的有效和选择性拮抗剂，目前正在研究用于支气管哮喘的治疗。为了评估孟鲁司特的代谢和排泄，6名健康受试者接受单次口服[14C]孟鲁司特102 mg，并收集尿液和粪便。大部分放射性在粪便中恢复，尿液中出现</=0.2%。根据这些结果和孟鲁司特中度高的口服生物利用度的报道，可以得出结论，大部分放射性是通过胆汁排出的。第二项临床研究是为了鉴定孟鲁司特的胆道代谢物。在口服54.8 mg [14C]孟鲁司特后，使用一种改进的方法将鼻胃管置于Vater壶腹附近，在透视下吸入胆汁。这项技术似乎是药物代谢研究的新应用。该研究在禁食和非禁食的受试者中进行，分别在给药后2-8小时和8-12小时的时间内持续吸取胆汁。收集程序结束前2小时，静脉注射胆囊收缩素羧基末端八肽以刺激胆囊收缩。血浆样本也定期收集超过10小时。由于收集程序的性质和有限的采样时间，胆汁中放射性的恢复是不完整的，从剂量的3%到20%不等。胆汁的放射色谱和LC-MS/MS分析显示存在一种主要代谢物和几种次要代谢物，以及少量不变的母体药物。通过与合成标准物的LC-MS/MS比较或核磁共振鉴定，次要代谢产物为孟鲁司特类似物的酰基葡萄糖醛酸酯（M1）、亚砜（M2）、25-羟基（a酚，M3）、21-羟基（苯基醇的非对映体M5a和M5b）和36-羟基（甲醇的非对映体M6a和M6b）。主要代谢物表征为二羧酸（M4），是羟甲基代谢物M6进一步氧化的产物。手性LC-MS/MS分析表明，M4与M5和M6一样，均以非对映体形式形成。摄食和禁食受试者的体循环代谢物水平均较低，代谢产物M5a、M5b、M6a和M6b在循环放射性中所占比例<2%。总的来说，这种胆汁抽吸技术比t管引流或细针经皮穿刺侵入性小，提供了一种方便和便捷的方法来鉴定孟鲁司特的胆道代谢产物，相对而言不受结肠微生物群的影响。
Montelukast sodium [1-([(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl)cyclopropylacetic acid sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene (Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was recovered in feces, with </=0.2% appearing in urine. Based on these results and the reported modestly high oral bioavailability of montelukast, it could be concluded that a major part of the radioactivity was excreted via bile. A second clinical study was conducted to identify biliary metabolites of montelukast. The bile was aspirated using a modified procedure involving a nasogastric tube placed fluoroscopically near the ampulla of Vater, after an oral dose of 54.8 mg of [14C]montelukast. This technique appears to be a new application for drug metabolism studies. The study was conducted with fasted and nonfasted subjects, with the bile being aspirated continuously under suction over periods of 2-8 hr and 8-12 hr after the dose, respectively. Two hours before the end of the collection procedure, cholecystokinin carboxyl-terminal octapeptide was administered iv to stimulate gallbladder contraction. Plasma samples also were collected periodically over 10 hr. Due to the nature of the collection procedure and the limited sampling time, recovery of radioactivity in bile was incomplete and varied from 3 to 20% of the dose. Radiochromatographic and LC-MS/MS analyses of bile showed the presence of one major and several minor metabolites, along with small amounts of unchanged parent drug. The minor metabolites were identified, by LC-MS/MS comparison with synthetic standards or by NMR, as acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydroxy (diastereomers of a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) analogs of montelukast. The major metabolite was characterized as a dicarboxylic acid (M4), a product of further oxidation of the hydroxymethyl metabolite M6. Chiral LC-MS/MS analyses of M4 revealed that this diacid, like M5 and M6, was formed in both diastereomeric forms. The levels of metabolites in the systemic circulation were low in the fed as well as fasted subjects, with <2% of the circulating radioactivity being due to metabolites M5a, M5b, M6a, and M6b. Overall, this bile aspiration technique, which is less invasive than either T-tube drainage or fine-needle percutaneous puncture, provided a convenient and expedient means of identifying the biliary metabolites of montelukast, relatively free of contributions from colonic microflora.