Abstract
Purpose: To develop a simple, adequately sensitive, and practical liquid chromatographic-mass spectrometric method to simultaneously quantify three tyrosine kinase inhibitors, viz, tofacitinib (TOF), cabozantinib (CBZ) and afatinib (AFB) after their extraction from both human plasma and urine. Methods: Blood and urine samples were obtained from healthy volunteers who admitted to not being on any medications. The investigated analytes were chromatographically separated on a C18 column (Luna ® -PFP 100A column, 50 mm × 2.0 mm i.d., 3.0 μm) with the aid of a mobile phase containing A; acetonitrile (ACN) and B; 0.01 M ammonium formate buffer (pH 4.1) pumped at a rate of 0.3 mL.min -1 in the ratio A:B, 50:50 v/v. Analyte monitoring was achieved by tandem mass spectrometry interfaced with an electrospray ionization source with the aid of multiple reaction monitoring (MRM) mode for analytes quantification. Results: The proposed method permitted a specific and sensitive determination of the investigated TKIs in the linear range of 1.0 - 100 ng mL -1 with correlation coefficient (r 2 ) of 0.9991, 0.9997, and 0.9998 for TOF, CBZ and AFB, respectively. The method was validated with regard to its limits of quantification (ranging from 0.91 to 1.24 ng mL -1 for the 3 analytes), intra- and inter assay accuracy (in the range -1.85 to 1.22 %) and precision (0.71 - 5.12 %). The method was also validated in terms of recovery from both studied matrices, robustness and matrix effect. Conclusion: The results obtained reveal that the developed method is simple, specific and highly efficient for routine determination of the studied analytes in human plasma and urine. It can be reliably applied for high throughput analysis of clinical samples containing the investigated analytes. Keywords: Tyrosine kinase inhibitors, Tofacitinib, Cabozantinib, Afatinib, LC-MS/MS, human plasma
Highlights
Tyrosine kinases (TKs) are deemed potential targets for new drug development, especially for cancer and rheumatoid arthritis drugs
In the current study a simple analytical procedure was designed to be able to simultaneously quantify various tyrosine kinase inhibitors (TKIs) in human plasma, three Food and Drug Administration (FDA) approved medications were selected as representative examples of the TKIs acting on the different kinases
The second chosen TKI representative is cabozantinib (CBZ; Fig. 1b)), which is an orally active agent that blocks the activity of different tyrosine kinases including mesenchymal–epithelial transition factor (MET) and vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3) [7]
Summary
Tyrosine kinases (TKs) are deemed potential targets for new drug development, especially for cancer and rheumatoid arthritis drugs. Several tyrosine kinase inhibitors (TKIs) have been developed and approved for the treatment of various types of cancer, with each of them targeting specific signaling pathways [1,2]. Afatinib (AFB; Fig 1a), a selective TKI that blocks the signaling pathways from the receptor tyrosine kinases HER1 (EGFR/ErbB1), HER2 (ErbB2), and HER4 (ErbB4) [5]. The second chosen TKI representative is cabozantinib (CBZ; Fig. 1b)), which is an orally active agent that blocks the activity of different tyrosine kinases including mesenchymal–epithelial transition factor (MET) and vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3) [7]. TOF is reported to selectively block the signaling pathway involving the kinases JAK 1 and 3 [8]. TOF was approved by the U.S FDA in 2012 for the management of patients with moderate to severe rheumatoid arthritis (RA) either alone or to be taken with methotrexate in more sever un-responsive cases [9]
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