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Development and validation of a sensitive LC-MS/MS method for the quantitation of IMB-YH-4py5-2H, an antituberculosis candidate, and its application to the pharmacokinetic study.
- Source :
-
PLoS ONE . 2/19/2020, Vol. 15 Issue 2, p1-13. 13p. - Publication Year :
- 2020
-
Abstract
- (E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 μm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1−100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 15
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 141823387
- Full Text :
- https://doi.org/10.1371/journal.pone.0228797