الفهرس 
Investigation of the metabolic profile of selected anticancer tyrosine kinase inhibitors by liquid chromatography mass spectroscopy
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Abstract
Incubation for the selected TKIs with RLMs alone or in the presence of KCN was done. Cyclic tertiary amine rings (N-methyl piperazine in PNT and MST, and N-methyl piperidine ring in VNT) were bioactivated and formed adducts with KCN. These reactive adducts may be responsible for the observed side effects of PNT and VNT in humans, and MST in animals and humans. Development of validated LC-MS/MS methods were done and applied to metabolic stability estimation. The low intrinsic clearance (3.91 and 3.0 mL/min/kg) with long in vitro t1/2 (40 min and 50 min.) of RLMs to metabolize VNT and MST, respectively suggested that VNT and MST are slowly cleared from the blood by the liver and thus considered as low extraction ratio drugs. The low intrinsic clearance of liver to metabolize VNT and MST is a specific character for the cited drugs not a general feature to similar TKIs as CLint for PNT was 15 mL/min/kg with short in vitro t1/2 of approximately 6 min. In vivo metabolism for the cited drugs were done. All the studied TKIs are partially excreted in the rat urine. Many oxidized metabolites were detected in rat urine for the cited drugs