Determination of Crizotinib in Mouse Tissues by LC-MS/MS and Its Application to a Tissue Distribution Study
Fang Zhao1,2, Yuan Wei1, Yiming Yan1
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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.
Insights
Crizotinib, a tyrosine kinase inhibitor, accumulates in mouse lungs, liver, spleen, and gastrointestinal tract. This study developed a validated LC-MS/MS method to quantify crizotinib tissue distribution, aiding toxicity research.
Area of Science:
- Pharmacology
- Analytical Chemistry
- Toxicology
Background:
- Crizotinib (a small-molecule tyrosine kinase inhibitor) toxicity is a clinical concern.
- Understanding crizotinib's tissue distribution is crucial for assessing its toxicity.
- A validated analytical method is needed for accurate quantification in biological matrices.
Purpose of the Study:
- To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining crizotinib concentrations in mouse tissues.
- To investigate the tissue distribution profile of crizotinib in mice.
- To provide a reliable quantification method for future crizotinib toxicity studies.
Main Methods:
- Mouse tissue homogenates were prepared using protein precipitation with methanol.
- Apatinib was used as the internal standard.
- Crizotinib was quantified using LC-MS/MS with a Phenomenex Kinetex C18 column and gradient elution, with carryover effects resolved.
Main Results:
- A validated LC-MS/MS method was successfully developed and applied to mouse tissues.
- The study determined the tissue distribution of crizotinib for the first time.
- High crizotinib concentrations were observed in the lung, liver, spleen, and gastrointestinal tract.
Conclusions:
- The developed LC-MS/MS method is reliable for quantifying crizotinib in mouse tissues.
- Crizotinib primarily distributes to the lung, liver, spleen, and gastrointestinal tract.
- This research provides essential data for understanding crizotinib-induced toxicity.
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