Simultaneous Quantification of Brigatinib and Brigatinib-Analog in Rat Plasma and Brain Homogenate by LC-MS/MS: Application to Comparative Pharmacokinetic and Brain Distribution Studies.

Bo Li,Shan Xiong,Suhong Chen,Maoen Zheng,Shanshan Lei,Min Lu,Peilu Sun,Lei Jin

doi:10.1155/2019/9028309

Abstract

Brigatinib and brigatinib-analog are potent and selective ALK inhibitors with the similar structure. A simple and sensitive high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of brigatinib and brigatinib-analog in rat plasma and brain homogenate was developed and validated. Chromatographic separation was carried out on an ODS column with acetonitrile and 0.1% formic acid in water as the mobile phase with gradient elution at a flow rate of 0.5 mL/min. Detections were performed using a TSQ Quantum Ultra mass spectrometric detector with electrospray ionization (ESI) interface, which was operated in the positive ion mode. A simple protein precipitation preparation process was used. The lower limits of quantification (LLOQs) were 1.0 ng/mL and 0.5 ng/mL for analytes in rat plasma and brain homogenate, respectively. The intrabatch and interbatch precision and accuracy of brigatinib and brigatinib-analog were well within the acceptable limits of variation. The simple and sensitive LC-MS/MS method was successfully applied to the pharmacokinetic and brain distribution studies following a single oral administration of brigatinib and brigatinib-analog to rats. The above studies would lay a good foundation for the further applications of brigatinib and brigatinib-analog.

Highlights

Lung cancer is one of the most commonly diagnosed tumors with high morbidity and mortality worldwide [1], and its incidence and mortality continue to grow
Lung cancer is divided into small-cell lung cancer (SCLC) and non-smallcell lung cancer (NSCLC), of which NSCLC accounts for 85% of lung cancer, including squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated cancer [2, 3]
Mass Spectra. e analytes and IS were found to respond best to positive ionization with the adduct ions [M + H]+, which were presented as the major peaks. eir product ion mass spectra are shown in Figure 1. e selected reaction monitoring (SRM) mode was used to monitor the transitions of m/z 584.26 ⟶ 484.08 for brigatinib, m/z 529.05 ⟶ 483.92 for brigatinib-analog, and m/z 500.24 ⟶ 71.89 for IS

Summary

Introduction

Lung cancer is one of the most commonly diagnosed tumors with high morbidity and mortality worldwide [1], and its incidence and mortality continue to grow. Lung cancer is divided into small-cell lung cancer (SCLC) and non-smallcell lung cancer (NSCLC), of which NSCLC accounts for 85% of lung cancer, including squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated cancer [2, 3]. Compared with SCLC, NSCLC has slower metastasis and proliferation. About 75% of NSCLC patients were found to be at the middle and late stages, and the 5-year reported survival rate was extremely low [4, 5]. E development of molecular research in the nearly ten years has meant significant breakthroughs in the diagnosis, detection, and treatment of lung cancer of the NSCLC. Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor family, was originally identified as a part of the fusion protein nucleophosmin-

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Conclusion