An ultra-fast green ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of zotizalkib in human liver microsomes.
Mohamed W AttwaAli Saber AbdelhameedAdnan A KadiPublished in: Journal of separation science (2024)
Zotizalkib (ZTK, TPX-0131) is a fourth-generation highly effective inhibitor of wild-type anaplastic lymphoma kinase (ALK) and ALK-resistant mutations that can penetrate the central nervous system. It exhibited greater potency compared to all five officially approved ALK inhibitors. The aim of this study was to develop a rapid, accurate, eco-friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for measuring the concentration of ZTK in human liver microsomes (HLMs). The validation aspects of the current UHPLC-MS/MS methodology in the HLMs were conducted in accordance with the bioanalytical method validation standards specified by the US Food and Drug Administration. ZTK and encorafenib were separated using an Agilent C8 column (Eclipse Plus) and an isocratic mobile phase. The calibration curve for the developed ZTK exhibited a linear relationship within the concentration range of 1-3000 ng/mL. The results from the Analytical Green-ness Metric Approach program (0.76) suggested that the created method demonstrated a significant degree of environmental sustainability. The in vitro half-life (t 1/2 ) and intrinsic clearance (Cl int ) of ZTK were determined to be 15.79 min and 51.35 mL/min/kg, respectively that suggests the ZTK exhibits characteristics similar to those of a medication with a high extraction ratio. These approaches are crucial for the progress of novel pharmaceutical development, especially in improving metabolic stability.
Keyphrases
- ultra high performance liquid chromatography
- tandem mass spectrometry
- simultaneous determination
- liquid chromatography tandem mass spectrometry
- liquid chromatography
- solid phase extraction
- ms ms
- high performance liquid chromatography
- high resolution
- high resolution mass spectrometry
- drug administration
- mass spectrometry
- gas chromatography
- molecularly imprinted
- advanced non small cell lung cancer
- wild type
- diffuse large b cell lymphoma
- healthcare
- quality improvement
- human health
- cerebrospinal fluid
- climate change
- risk assessment
- emergency department
- living cells