Abstract
VS-5584 is a small-molecular compound that showed equivalent activity against mTOR and all class I PI3K isoforms and demonstrated preclinical activity in diverse cancer cell lines and xenograft tumor model, and rational combination of VS-5584 and other target therapies achieved promising outcomes in oncology. In the present study, we established and validated a simple and sensitive UPLC-MS/MS method for the determination of VS-5584 in plasma samples. VS-5584 was separated via an Acquity UPLC BEH C18 column, with a mobile phase composed of acetonitrile and 0.2% formic acid in water (40 : 60). The calibration curve displayed a good linearity in the range of 1.0–1000 ng/mL, with satisfactory accuracy (−13.6% < RE% < 8.8%) and precision (CV%, less than 9.2%). The validated method was then applied to a pharmacokinetic study in rats. After administration of 10 mg/kg, VS-5584 was absorbed quickly and reached a peak concentration of 473.2 ± 72.0 ng/mL after 20 min. The established method allows for the quantification of VS-5584 in rat plasma in detail and can be utilized to successfully describe the pharmacokinetic profile of VS-5584.
Highlights
VS-5584 is a small-molecular inhibitor that shows equivalent activity against mTOR and all four class I phosphoinositide 3-kinase (PI3K) isoforms [6]
Numerous findings support the clinical development of VS-5584, no detailed analytical method of VS5584 detection has been reported, and no pharmacokinetic study has been performed
As LC-MS/MS is widely used for the detection of small molecules in biological matrices [18, 19], we established and validated a simple and sensitive ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for the quantification of VS5584 levels in rat plasma. e pharmacokinetic profile after oral administration of VS-5584 in adult male Sprague Dawley (SD) rats was investigated
Summary
VS-5584 is a small-molecular inhibitor that shows equivalent activity against mTOR and all four class I PI3K isoforms [6]. It can permeate cells, including PC3, NCl-N87, HuH7, Colo205, and MDA-MB-231, to modulate signalling pathways downstream of the PI3K/mTOR pathways [7]. In a preclinical xenograft model of pancreatic ductal adenocarcinoma, the combination therapy with an ERK inhibitor SCH772984 increased the tumor suppression rate to 80% compared with VS-5584 treatment alone (28%) [14]. Journal of Analytical Methods in Chemistry cells (CSCs) [16, 17], VS-5584 suppressed cisplatin-resistant CSC growth and delayed tumor regrowth after cessation of cisplatin treatment in xenograft models of small cell lung cancer [16]. As LC-MS/MS is widely used for the detection of small molecules in biological matrices [18, 19], we established and validated a simple and sensitive ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for the quantification of VS5584 levels in rat plasma. e pharmacokinetic profile after oral administration of VS-5584 in adult male Sprague Dawley (SD) rats was investigated
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