A validated LC–MS/MS method for the determination of RAF inhibitor LXH254: Application to pharmacokinetic study in rat
| Autor: | Wu Zhong, Meiping Ren, Rong Li, Wei Lu, Yunhua Yuan, Jian Li |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Niacinamide Formic acid Clinical Biochemistry Ethyl acetate Administration Oral Biological Availability Sensitivity and Specificity 030226 pharmacology & pharmacy 01 natural sciences Biochemistry Analytical Chemistry Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Stability Pharmacokinetics Tandem Mass Spectrometry Drug Discovery Animals Enzyme Inhibitors Molecular Biology Chromatography High Pressure Liquid Pharmacology Chromatography 010401 analytical chemistry Extraction (chemistry) Selected reaction monitoring Reproducibility of Results General Medicine Rats 0104 chemical sciences Triple quadrupole mass spectrometer Bioavailability chemistry Linear Models Administration Intravenous raf Kinases Ammonium acetate |
| Zdroj: | Biomedical Chromatography. 35 |
| ISSN: | 1099-0801 0269-3879 |
| Popis: | In this study, a simple and sensitive UHPLC-ESI-MS/MS method was established for the determination of LXH254 in rat plasma. The developed method was validated according to the Food and Drug administration guidelines. After extraction using ethyl acetate, the sample was separated on an ACQUITY BEH C18 column. The mobile phase consisted of 2 mM ammonium acetate containing 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. The flow rate was 0.3 mL/min. A TSQ triple quadrupole mass spectrometer operated in positive-ion mode was used for mass detection, with multiple reaction monitoring transitions of m/z 503.3 > 459.1 and m/z 435.3 > 367.1 for LXH254 and olaparib (internal standard), respectively. An excellent linearity was achieved in the concentration range of 0.1-1000 ng/mL, with correlation coefficient >0.998. The mean recovery was more than 78.55%. Inter- and intra-day precision (percentage of relative standard deviation) did not exceed 12.87%, and accuracy was in the range of -2.50 to 13.50%. LXH254 was demonstrated to be stable under the tested storage conditions. The validated UHPLC-MS/MS method was further applied to the pharmacokinetic study of LXH254 in rat plasma after oral (2, 5, and 15 mg/kg) and intravenous (2 mg/kg) administrations. The pharmacokinetic study revealed that LXH254 showed low clearance, moderate bioavailability (~30%), and linear pharmacokinetic profile over the oral dose range of 2-15 mg/kg. To the best of our knowledge, this is the first report on the method development and validation of the determination of LXH254 and its application to pharmacokinetic study. |
| Databáze: | OpenAIRE |
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