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A rapid and sensitive LC‐MS/MS method for evaluation of the absolute oral bioavailability of a novel c‐Met tyrosine kinase inhibitor QBH‐196 in rats
Author(s) -
Zhang Qi.,
Sun Jin,
Lu Tianshu,
Zhang Jinling,
Wu Chunnuan,
Li Lin,
He Zhonggui,
Zhao Yanfang,
Liu Xiaohong
Publication year - 2015
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.3474
Subject(s) - chemistry , chromatography , extraction (chemistry) , bioavailability , electrospray ionization , mass spectrometry , pharmacology , medicine
A sensitive, selective and high‐throughput UPLC‐MS/MS method was developed and validated for the determination of a novel c‐Met tyrosine kinase inhibitor, QBH‐196, in rat plasma. QBH‐196 and its analog BH357 (IS) were extracted from rat plasma using a mixture of dichloromethane and N ‐hexane (2:3, v/v). The chromatographic separation was carried out on Phenomenex C 18 column (50 × 2.1 mm, 2.6 µm particle size) with a gradient mobile phase of methanol (A) and water containing 0.05% formic acid (B) at a flow rate of 0.2 mL/min. The assay was performed by positive electrospray ionization in multiple reaction monitoring mode using transitions of m / z 622.68 → 140.41 for QBH‐196 and m / z 591.19 →126.21 for the IS, respectively. Good linearity was obtained over the concentration range of 8.0–4000 ng/mL ( r 2 > 0.99) for QBH‐196 and the lower limit of quantification was 8.0 ng/mL in rat plasma. Validations of the method, including its sensitivity, extraction recovery, matrix effect, intra‐ and inter‐day precision, accuracy and stability, were all within acceptable limits. The established method was successfully applied to determine absolute oral bioavailability of QBH‐196 in rats for the first time. The mean oral absolute bioavailability of QBH‐196 was found to be about 40.8% and the elimination half‐life was 40.0 ± 13.1 h. This result suggested that QBH‐196 exhibits good oral absorption in vivo , which is very important for the further development of QBH‐196 as a new oral anticancer drug. Copyright © 2015 John Wiley & Sons, Ltd.