title: Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by stereoselective high-performance liquid chromatography with column-switching.
abstract: A steoreoselective high-performance liquid chromatographic method was developed for the quantification of montelukast (free acid of Singulair, or MK-0476), a potent and selective leukotriene D4 (cysLT1) receptor antagonist, and it S-enantiomers (L-768,232). The method involves protein precipitation and fluorescence detection. Chromatographic separation of the enantiomers from endogenous components in plasma and chiral resolution of the enantiomers are achieved by using column switching HPLC and an alpha-acid glycoprotein chiral column. The assay is linear in the range of 28.9-386 ng ml-1 of free acids of montelukast and L-768,232. The intraday precision (% relative standard deviation) values of this method were in the range of 2.5-9.1% for montelukast, and 2.4-6.8% for L-768,232, while the intraday accuracy values were in the range of 97-103% for montelukast and 96-104% for L-768,232. The interday precision values of this method at 48.2 and 193 ng ml-1 were 5.3 and 3.6%, respectively, for montelukast, and 4.2 and 3.7%, respectively, for L-768,232, while the interday accuracy values at these concentrations were 97 and 103%, respectively, for montelukast and 99 and 102%, respectively, for L-768,232. The utility of the methodology was demonstrated by analysis of plasma samples from a study in which healthy volunteers received 10 mg per day of montelukast orally for 7 days. Results of this study indicate that there is no apparent bioinversion of montelukast to its S-enantiomer in humans.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: J J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: J D
authors.initials: JD
authors.lastname: Rogers
mesh_terms: D000085:Acetates / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods; D003521:Cyclopropanes; D006801:Humans; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines / Q000097:blood*; D018077:Receptors, Leukotriene; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013440:Sulfides
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C093875:montelukast