METABOLIC PROFILES OF MONTELUKAST SODIUM (SINGULAR), A POTENT CYSTEINYL LEUKOTRIENE(1) RECEPTOR ANTAGONIST, IN HUMAN PLASMA AND BILE

Montelukast sodium )-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl -hydroxy-1-methylethyl)phenyl)propyl)thio]-methyl} cyclopropylacetic a cid sodium salt] (MK-476, Singulair) is a potent and selective antagon ist of the cysteinyl leukotriene (Cys-LT1) receptor and is under inves tigation for the treatment of bronchial asthma. To assess the metaboli sm and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [C-14]montelukast, and the urine and feces wer e collected. Most of the radioactivity was recovered in feces, with le ss than or equal to 0.2% appearing in urine. Based an these results an d the reported modestly high oral bioavailability of montelukast, it c ould be concluded that a major part of the radioactivity was excreted via bile. A second clinical study was conducted to identify biliary me tabolites of montelukast. The bile was aspirated using a modified proc edure involving a nasogastric tube placed fluoroscopically near the am pulla of Vater, after an oral dose of 54.8 mg of [C-14]montelukast. Th is technique appears to be a new application for drug metabolism studi es. The study was conducted with fasted and nonfasted subjects, with t he 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 octape ptide was administered iv to stimulate gallbladder contraction. plasma samples also were collected periodically over 10 hr. Due to the natur e of the collection procedure and the limited sampling time, recovery of radioactivity in bile was incomplete and varied from 3 to 20% of th e close. 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 identifi ed, by LC-MS/MS comparison with synthetic standards or by MMR, as acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydro xy (diastereomers of a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) analogs of montelukas t. The major metabolite was characterized as a dicarboxylic acid (M4), a product of further oxidation of the hydroxymethyl metabolite M6. Ch iral LC-MS/MS analyses of M4 revealed that this diacid, like M5 and M6 , was formed in both diastereomeric forms. The levels of metabolites i n the systemic circulation were low in the fed as well as fasted subje cts, with <2% of the circulating radioactivity being due to metabolite s M5a, M5b, M6a, and M6b. Overall, this bile aspiration technique, whi ch is less invasive than either T-tube drainage or fine-needle percuta neous puncture, provided a convenient and expedient means of identifyi ng the biliary metabolites of montelukast, relatively free of contribu tions from colonic microflora.