Pharmacokinetic Analysis of Montelukast in Healthy Korean Volunteers by High Performance Liquid Chromatography-Tandem Mass Spectrometry

Abstract

− A rapid and specific high performance liquid chromatography-tandem mass (LC/MS/MS) method for the analysis of montelukast in human plasma has been developed and validated. After cold acetonitrile-induced precipitation of the plasma samples, montelukast and glipizide (internal standard, IS) were eluted on a reverse-phase C 18 column by isocratic mobile phase consisted of 10 mM ammonium formate buffer (adjusted to pH 3.5 with formic acid) and acetonitrile (3:97, v/v). Acquisition was performed with multiple reaction monitoring (MRM) mode by monitoring the transitions: m/z 587.2→ 423.2 for montelukast and m/z 446.0→321.2 for IS. Ranges of concentration for calibration curves (10-1000 ng/mL) showed correlation coefficients (r 2 ) were better than 0.9948. Precision of intra-and inter-day ranged from 3.70 to 11.68% and from 3.04 to 12.95%, accuracy of intra-day and inter-day ranged from 93.34 to 102.75% and from 100.79 to 107.63%, respectively. The described method provides a fast and sensitive analytical tool for determining montelukast levels in plasma, and was successfully applied to a pharmacokinetic study in 16 healthy human subjects after oral administration of 10mg tablet formulation of montelukast sodium under fasting conditions. Key words − Montelukast, Pharmacokinetic study, Human plasma, LC/MS/MS, KoreanMontelukast, (S, E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-(2-hydroxy propan-2-yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid, is antihistamic drug as a leukotrien receptor antagonist for using treatment of seasonal allergy and chronic asthma (Mastalerz et al., 2010;Castro-Rodriguez et al., 2010;Yasar et al., 2011;Schäper et al., 2011).Several groups have reported methods for the determination of montelukast in biological matrices. These methods include chromatographic assay (Amin et al., 1995;Liu et al., 1997; AlRawithi 2001), usage of dual column (Smith et al., 2004), column switching (Ochiai et al., 1998), spectrofluorometry (Alsarra et al., 2005) or mass spectrometry (Challa et al., 2010;Sripalakit et al., 2008). However, most of these methods required laborious sample pretreatment or derivatization, and long chromatographic run times, and thus, are not convenient for analyzing the large numbers of samples generated during pharmacokinetic research. Thus, in the present study, our objective was to develop a rapid, sensitive, high throughput method for the routine determination of montelukast in human plasma.Pharmacokinetic studies of montelukast were performed in various laboratories. In case of oral administration of 10 mg film-coated tablet, it was reported the T max, AUC 0-t and C max was 3.7 ± 0.8 hr, 2441 ± 441 ng·hr/mL and 385 ± 85 ng/mL, respectively (Cheng et al., 1996). Challa BR et al. reported pharmacokinetic research in 31 healthy Indians volunteers after oral administration of 5 mg montelukast; AUC 0-t , C max and T max are decided to be 2417.26 ± 63.58 ng·hr/mL, 369.29 ± 137.35 ng/mL and 2.67 hr, respectively. Meanwhile other group (Sripalakit et al....