Abstract
Toxicity induced by crizotinib, a small-molecule tyrosine kinase inhibitor, is a significant clinical issue during treatment. A tissue distribution study is required to explore the organs affected by this molecule. In this study, a simple liquid chromatography tandem mass spectrometry method was developed and validated for the determination of crizotinib in various mouse tissues. Mouse tissue homogenates were processed by protein precipitation with methanol, and apatinib was chosen as the internal standard. The analytes were separated on a Phenomenex Kinetex C18 (50 mm × 2.1 mm, 2.6 μm) column with gradient elution using methanol and 0.3% formic acid water solution. Tandem mass spectrometric detection was conducted using multiple reaction monitoring via an electrospray ionization source in the positive mode. The monitored ion transitions were m/z 450.1 ⟶ 260.2 for crizotinib and m/z 398.2 ⟶ 212.0 for apatinib. The problem of the severe carryover effect was successfully resolved. The method was validated and applied to a tissue distribution study of crizotinib in mice, which was reported for the first time. The results of the study showed that the main target organs of crizotinib were the lung, liver, and spleen, and a high concentration of crizotinib was found in the gastrointestinal tract. This study offers a reliable method for quantifying crizotinib and provides a basis for further research on crizotinib toxicity.
Highlights
Crizotinib (Figure 1(a)) is an oral multitargeted receptor tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and hepatocyte growth factor MET receptor tyrosine kinases [1, 2]
Crizotinib was approved by the Food and Drug Administration (FDA) as a first-line treatment of ALKrearranged nonsmall cell lung cancer (NSCLC) in 2011 [1] and was approved in the United States and European Union for the therapy of patients with ROS1-positive advanced NSCLC in 2016 [3]
To optimize the mass spectrometric conditions, the standard solutions of crizotinib and IS were injected into the mass spectrometer. e positive-ion electrospray ionization (ESI) mode was performed, considering that nitrogen is present in the chemical structures of crizotinib
Summary
Crizotinib (Figure 1(a)) is an oral multitargeted receptor tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and hepatocyte growth factor MET receptor tyrosine kinases [1, 2]. Crizotinib was approved by the FDA as a first-line treatment of ALKrearranged nonsmall cell lung cancer (NSCLC) in 2011 [1] and was approved in the United States and European Union for the therapy of patients with ROS1-positive advanced NSCLC in 2016 [3]. Crizotinib remains the only approved, standard first-line therapy for ROS1-rearranged NSCLC [4, 5] and is highly effective in the clinic [6]. It represents a clinically meaningful treatment option for NSCLC with MET alterations [2]. To explore the mechanism of its toxicity and preventive measures, it is necessary to investigate the tissue distribution of crizotinib at toxic doses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
