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Effect of rat enzymes on the metabolism of tyrosine kinase inhibitors in vitro and in vivo
Škriabová, Simona ; Indra, Radek (advisor) ; Ptáčková, Renata (referee)
Tyrosine kinase inhibitors are small molecules, orally available, well-tolerated and globally approved drugs for the treatment of several types of tumors. These drugs include vandetanib, cabozantinib, and lenvatinib, which are used to treat thyroid cancer. Vandetanib and cabozantinib are drugs approved for the treatment of medullary thyroid cancer, and lenvatinib is approved for the treatment of differentiated thyroid cancer. In the presented diploma thesis, the in vitro and in vivo metabolism of vandetanib, cabozantinib and lenvatinib was studied. Microsomes isolated from the liver of rats premedicated with pregnenolone carbonitrile were used to study in vitro metabolism. Plasma and urine samples of rats premedicated with individual tyrosine kinase inhibitors were used to study in vivo metabolism. The resulting metabolites were analyzed by high-performance liquid chromatography and subsequently identified using the mass spectrometry method. In the study of in vitro metabolism, when NADPH and cofactors (glucuronic acid and glutathione) were added to the samples, it was found that the most metabolites appeared for all three drugs during a longer incubation periods, and at the same time, it was found that glucuronic acid and glutathione can influence the structure, properties and functions of the...
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