Generic placeholder image

Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

A Rapid and Selective UPLC-MS/MS Assay for Accurate Analysis of Apatinib in Rat Plasma and its Application to a Pharmacokinetic Study

Author(s): Jinglin Gao, Zhangying Feng, Huan Ren, Mengdi Yu, Haidong Wang and Mingxia Wang*

Volume 17, Issue 5, 2021

Published on: 06 February, 2020

Page: [594 - 602] Pages: 9

DOI: 10.2174/1573412916666200206143836

Price: $65


Objective: Apatinib, a novel small-molecule Tyrosine Kinase Inhibitor (TKI), is under development to treat advanced gastric cancer. For the pharmacokinetic evaluation and routine drug monitoring of apatinib, a quantitative ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method in rat plasma was developed with tinidazole used as an internal standard (IS).

Methods: Protein precipitation (PPT) was selected as a sample pre-treatment method to extract apatinib. Then, chromatography was performed on a Kinetex C8 column (2.1×100 mm, 2.6 μm) using a constant mobile phase including 0.2% formic acid and 10 mM ammonium acetate in water and methanol (30:70, v/v) with a gradient flow rate from 0.2 mL/min to 0.4 mL/min. Chromatographic analysis was performed in only 4.5 min. Mass spectrometric detection was carried on positive electrospray ionization (ESI+) mode with Multiple-Reaction Monitoring (MRM).

Results: The standard calibration curve showed good linearity in 2-1000 ng/mL with the correlation coefficient (R2) > 0.99. The Lower Limit of Quantitation (LLOQ) was 2 ng/mL. The precision, accuracy, extraction recovery, matrix effect, stability and carryover were all within the acceptable range.

Conclusion: This method was simple, accurate, selective and successfully used for a pharmacokinetic study following seven rats orally administrated a single of 60 mg/kg apatinib.

Keywords: Apatinib, UPLC-MS/MS, rat plasma, pharmacokinetics, protein precipitation, method development, validation.

Graphical Abstract
Ding, J.; Chen, X.; Dai, X.; Zhong, D. Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 895-896, 108-115.
[] [PMID: 22503745]
Tian, S.; Quan, H.; Xie, C.; Guo, H.; Lü, F.; Xu, Y.; Li, J.; Lou, L. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci., 2011, 102(7), 1374-1380.
[] [PMID: 21443688]
Feng, S.; Zhang, J.; Wang, Y.; Sun, R.; Feng, D.; Peng, Y.; Yang, N.; Zhang, Y.; Gao, H.; Gu, H.; Wang, G.; Aa, J.; Zhou, F. Application of liquid chromatography-tandem mass spectrometry to study the effect of docetaxel on pharmacokinetics and tissue distribution of apatinib in mice. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2018, 1083, 198-203.
[] [PMID: 29549743]
Ji, G.; Hong, L.; Yang, P. Successful treatment of angiosarcoma of the scalp with apatinib: a case report. OncoTargets Ther., 2016, 9, 4989-4992.
[] [PMID: 27563253]
Bao, S.S.; Wen, J.; Zheng, X.; Zhou, Q.; Qu, G.E.; Chen, M.J.; Hu, G.X. Evaluation of the inhibition effects of apatinib on human and rat cytochrome P450. Toxicol. Lett., 2018, 297, 1-7.
[] [PMID: 30138636]
Hu, X.; Cao, J.; Hu, W.; Wu, C.; Pan, Y.; Cai, L.; Tong, Z.; Wang, S.; Li, J.; Wang, Z.; Wang, B.; Chen, X.; Yu, H. Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer. BMC Cancer, 2014, 14, 820-820.
[] [PMID: 25376790]
Geng, R.; Li, J. Apatinib for the treatment of gastric cancer. Expert Opin. Pharmacother., 2015, 16(1), 117-122.
[] [PMID: 25420417]
Li, J.; Qin, S.; Xu, J.; Guo, W.; Xiong, J.; Bai, Y.; Sun, G.; Yang, Y.; Wang, L.; Xu, N.; Cheng, Y.; Wang, Z.; Zheng, L.; Tao, M.; Zhu, X.; Ji, D.; Liu, X.; Yu, H. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J. Clin. Oncol., 2013, 31(26), 3219-3225.
[] [PMID: 23918952]
Hu, X.; Zhang, J.; Xu, B.; Jiang, Z.; Ragaz, J.; Tong, Z.; Zhang, Q.; Wang, X.; Feng, J.; Pang, D.; Fan, M.; Li, J.; Wang, B.; Wang, Z.; Zhang, Q.; Sun, S.; Liao, C.; Shao, Z.M. Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer. Int. J. Cancer, 2014, 135(8), 1961-1969.
[] [PMID: 24604288]
Qin, S. Apatinib in Chinese patients with advanced hepatocellular carcinoma: a phase II randomized, open-label trial. J. Clin. Oncol., 2014, 32, 17-20.
Li, J.; Zhao, X.; Chen, L.; Guo, H.; Lv, F.; Jia, K.; Yv, K.; Wang, F.; Li, C.; Qian, J.; Zheng, C.; Zuo, Y. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer, 2010, 10, 529.
[] [PMID: 20923544]
Yu, M.; Gao, Z.; Dai, X.; Gong, H.; Zhang, L.; Chen, X.; Zhong, D.F.; Sy, S.K. Population pharmacokinetic and covariate analysis of apatinib, an oral tyrosine kinase inhibitor, in healthy volunteers and patients with solid tumors. Clin. Pharmacokinet., 2017, 56(1), 65-76.
[] [PMID: 27379402]
Liu, X.Y.; Zhang, Y.F.; Chen, Q.; Zhan, Y.; Wang, Q.R.; Hu, C.Y.; Yu, C.; Guo, Z.T.; Chen, X.Y.; Zhong, D.F. Pharmacokinetic drug interactions of apatinib with rifampin and itraconazole. J. Clin. Pharmacol., 2017, 00, 1-10.
[PMID: 28967981]
Ni, M.W.; Zhou, J.; Li, H.; Chen, W.; Mou, H.Z.; Zheng, Z.G. Simultaneous determination of six tyrosine kinase inhibitors in human plasma using HPLC-Q-Orbitrap mass spectrometry. Bioanalysis, 2017, 9(12), 925-935.
[] [PMID: 28617069]
Guidance for Industry: Bioanalytical Method Validation, 2018.
Jin, X.; Zhou, F.; Liu, Y.; Cheng, C.; Yao, L.; Jia, Y.; Wang, G.; Zhang, J. Simultaneous determination of parecoxib and its main metabolites valdecoxib and hydroxylated valdecoxib in mouse plasma with a sensitive LC-MS/MS method to elucidate the decreased drug metabolism of tumor bearing mice. J. Pharm. Biomed. Anal., 2018, 158, 1-7.
[] [PMID: 29843006]
Guide for the care and use of laboratory animals, revised edition; Washington; Bethesda; MD, 1996.
Lou, D.; Qiao, L.M.; Cheng, C.; Zhang, H.; Hu, G.X. Determination and pharmacokinetic study of apatinib in rat plasma by UPLC. J. Chromatogr. Sci., 2016, 54(1), 17-21.
[PMID: 26194841]
Clouser-Roche, A.; Johnson, K.; Fast, D.; Tang, D. Beyond pass/fail: a procedure for evaluating the effect of carryover in bioanalytical LC/MS/MS methods. J. Pharm. Biomed. Anal., 2008, 47(1), 146-155.
[] [PMID: 18242037]
Wickremsinhe, E.R.; Ackermann, B.L.; Chaudhary, A.K. Validating regulatory-compliant wide dynamic range bioanalytical assays using chip-based nanoelectrospray tandem mass spectrometry. Rapid Commun. Mass Spectrom., 2005, 19(1), 47-56.
[] [PMID: 15570573]
Dziadosz, M.; Klintschar, M.; Teske, J. Imatinib quantification in human serum with LC-MS3 as an effective way of protein kinase inhibitor analysis in biological matrices. Drug Metab. Pers. Ther., 2017, 32(3), 147-150.
[] [PMID: 28787270]
Liu, D.; Jiang, J.; Hu, P.; Tan, F.; Wang, Y. Quantitative determination of icotinib in human plasma and urine using liquid chromatography coupled to tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2009, 877(30), 3781-3786.
[] [PMID: 19833564]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy