Abstract
Vandetanib (VNT) is a new oral tyrosine kinase inhibitor that acts mainly by inhibiting vascular endothelial growth factor receptor (VEGFR). Fast, specific, sensitive and validated LC–MS/MS was established for the determination of VNT in two various matrices including rat liver microsomes (RLMs) and human plasma. This method was applied in metabolic stability investigation of VNT. Resolution of two analytes was performed using C18 column and isocratic mobile phase composed of binary system of 10 mM ammonium formate (pH 4.1) and acetonitrile in a ratio of 1:1. The flow rate was set at 0.25 mL/min and total run time was 4 min with injection volume of 5 µL. Ions were generated by ESI source and analyzed by multiple reaction monitoring mode (basis for quantification) in the Agilent 6410 QqQ analyzer. The linearity of the established method ranged from 5 to 500 ng/mL (r2 ≥ 0.9996) in human plasma and RLMs. LOQ and LOD were 2.48 and 7.52 ng/mL, and 2.14 and 6.49 in human plasma and RLMs matrices. The intra-day and inter-day precision and accuracy were 0.66–2.66% and 95.05–99.17% in human plasma matrix while in RLMs matrix, ranged from 0.97 to 3.08% and 95.8 to 100.09%, respectively. In vitro half-life was 39.85 min and intrinsic clearance was 3.92 ± 0.28 mL/min/kg.
Highlights
Cancer is one of the leading reasons of death that results in More than one-fourth of the world’s deaths [1]
The goal of our work is to study the metabolic stability and clearance of VNT, and a new LC–MS/ MS method was established
The low intrinsic capacity of liver to metabolize VNT is a specific character for the cited drug not a general feature to similar Tyrosine kinase inhibitors (TKIs) as when we investigated the CLint and in vitro t1/2 of ponatinib in our previous article [16], we found that CLint was 15 mL/min/ kg with short in vitro t1/2 of approximately 6 min
Summary
Cancer is one of the leading reasons of death that results in More than one-fourth of the world’s deaths [1]. The management of disseminated cancer have lately been done by molecular targeting strategies, based on the examinations of the oncogenes and tumor suppressors contributed in the development of human cancers [2]. Tyrosine kinase inhibitors (TKIs) are an imperative novel class of targeted therapy which interfere with specific. VNT (Fig. 1) is a vascular endothelial growth factor receptor 2 (VEGFR) inhibitor [4]. VEGFR has gained importance as pharmacologic targets as a Tyrosine kinase receptors [5]. In 2011, VNT (Caprelsa® tablets; AstraZeneca Pharmaceuticals LP) was approved by the USFDA for management of various types of medullary thyroid cancer. It was the first drug approved for this case. Its toxicity profile includes prolongation of the QT interval and sudden death [6]
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