title: Trace-level quantitation of iralukast in human plasma by microbore liquid chromatography/tandem mass spectrometry.
abstract: Iralukast (CGP 45715A) is a potent peptido-leukotriene antagonist that is active in various in vitro and animal models for the treatment of asthma. An analytical challenge was to develop a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 10 pg/mL for the analysis of iralukast when administered at low doses during clinical trials. Several issues had to be addressed in order to devise a LC/MS/MS assay for the above compound. First, iralukast appeared to be light sensitive and unstable at room temperature under acidic conditions. Second, a LLOQ of 10 pg/mL was needed to support several clinical trials. Third, positive electrospray ionization of iralukast did not yield the necessary sensitivity required for studies in humans. Consequently, LC/MS/MS conditions were optimized for the negative ion mode of detection. Fourth, sample preparation steps proved to be critical to reduce the possibility of microbore HPLC column (50 mm x 1.0 mm i.d.) obstruction, chromatographic deterioration, and matrix-mediated electrospray ion suppression. While our validated method addressed the above challenges, its major drawback was limited sample throughput capability. Nonetheless, plasma concentration-time profiles for patients with moderate asthma after oral administration of 200, 500, 1000, and 5000 microgram/kg/day of iralukast were successfully obtained.
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA. tapan.majumdar@pharma.novartis.com
authors.forename: T K
authors.initials: TK
authors.lastname: Majumdar
authors.forename: R
authors.initials: R
authors.lastname: Bakhtiar
authors.forename: D
authors.initials: D
authors.lastname: Melamed
authors.forename: F L
authors.initials: FL
authors.lastname: Tse
mesh_terms: D018927:Anti-Asthmatic Agents / Q000097:blood* / Q000493:pharmacokinetics; D001578:Benzopyrans / Q000097:blood* / Q000493:pharmacokinetics; D002138:Calibration; D002853:Chromatography, Liquid; D005615:Freezing; D006801:Humans; D007202:Indicators and Reagents; D020024:Leukotriene Antagonists / Q000097:blood* / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D011786:Quality Control; D012015:Reference Standards; D012996:Solutions
chemical_list: D018927:Anti-Asthmatic Agents; D001578:Benzopyrans; D007202:Indicators and Reagents; D020024:Leukotriene Antagonists; D012996:Solutions; C067425:iralukast