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Effect of pH and other factors on the metabolic conversion of tyrosine kinase inhibitors.
Čillíková, Olívia ; Indra, Radek (advisor) ; Čermáková, Michaela (referee)
Targeted anti-tumor therapy is a modern and effective approach to cancer treatment. This type of therapy includes several groups of anticancer drugs. The second most commonly used group of targeted chemotherapeutic substances are tyrosinkinase inhibitors. These are small- molecular agents that target specific signalling pathways of the tumor cell, thereby inhibiting it's growth, proliferation and angiogenesis. Representatives of this drug group include vandetanib and sunitinib. Vandetanib is primarily used for the treatment of medullary thyroid cancer and sunitinib has been approved for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. The diploma thesis focuses on the effect of pH and temperature on the in vitro metabolism of vandetanib and sunitinib using first-phase biotrasnformation enzymes. Differently premedicated and control rat liver microsomes were used in the experiments. Human and rat recombinant cytochromes P450 were used for comparison. The primary purpose of the experiments was to find the experimental pH and temperature optimum of the in vitro metabolism of vandetanib and sunitinib. These experiments also investigated the effect of pH and temperature on the drugs themselves and their stability. The effect of pH and temperature on the metabolism of the...
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Effect of pH on vandetanib oxidation
Fedák, Michal ; Indra, Radek (advisor) ; Otáhalová, Barbora (referee)
Vandetanib is anticancer drug used mainly for targeted therapy of medullary thyroid carcinoma. It acts as inhibitor of tyrosine kinase and shows selectivity for vascular endothelial growth factor 2 (VEGFR-2) and epidermal growth factor (EGFR). It also inhibits rearranged during transfection (RET) tyrosine kinase activity. Vandetanib is metabolized by cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs) in organism of humans as well as experimental animals. CYPs oxidize vandetanib to N-desmethylvandetanib. FMOs are responsible for the formation of vandetanib N-oxide. This bachelor thesis studies effect of pH on vandetanib oxidation by CYPs a FMOs present in rat hepatic microsomes induced by different agents. Collected data show that in majority of series, optimal pH levels for oxidation of vandetanib by CYPs and FMOs are similar to a large extend. The highest amount of N- desmethylvandetanib was observed mostly at the pH 8,5. Vandetanib N-oxide was also produced in the highest quantity at the same level of pH in majority of series. Results suggest that N-desmethylvandetanib is formed at levels of pH which do not fit in interval of pH for optimal CYP activity. This finding is apparently due to a fact that presence of vandeanib in its neutral form, which is effectively oxidized by CYP,...
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The effect of tyrosinkinase inhibitors vandetanib and lenvatinib and cytotoxic alkaloid ellipticine on biotransformation enzymes
Baráčková, Petra ; Dračínská, Helena (advisor) ; Václavíková, Radka (referee)
In recent years, tyrosine kinase inhibitors have been widely used for the treatment of certain tumors as so-called targeted therapy. Many studies are concerned with their metabolism and the role of enzymes in the biotransformation process, but very little is known about the impact of tyrosine kinase inhibitors on the expression and activity of biotransformation enzymes. Nevertheless modification of the expression and activity of enzymes may cause adverse interactions of co-administered drugs and their negative impact on the human body. This diploma thesis studies the effect of tyrosine kinase inhibitors vandetanib and lenvatinib and cytotoxic alkaloid ellipticine on biotransformation enzymes in a rat model organism in vivo. The aim was to characterize the effect of the investigated compounds on gene expression, protein expression and activity of cytochromes P450 (CYP) 1A1, 1A2 and 1B1 and flavin-containing monooxygenases FMO1 and FMO3 in renal and hepatic microsomes. Microsomes and RNA were isolated from kidneys of control rats and the pretreated rats. Western blot and immunodetection was used to compare the protein expression levels of studied enzymes in kidney and liver. By reverse transcription, cDNA was prepared from isolated RNA and used as a template for quantitative PCR to compare the...
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Possible role of flavine monooxygenases in xenobiotic metabolism
Cikánová, Magdaléna ; Hudeček, Jiří (advisor) ; Hodek, Petr (referee)
Presented bachelor thesis is an overview of the most important facts about flavin-containing monooxygenases (FMOs) found in literary sources. FMOs are enzymes, which participate on oxygenation of many foreign compounds which are soft nucleophils, thus compounds containing mostly nitrogen in their molecules as well as sulfur and sometimes also phosphorus and selenium. FMOs use molecular oxygen in their catalytic cycle, which is similar to catalytic cycle of cytochome P- 450: one molecule of oxygen is activated by its reduction in presence of NADPH, one atom of oxygen is incorporated to substrate molecule, meanwhile the second one is reduced to water. In these days FMOs in mammals, bacteria, plants and yeast were described. Up to date five human genes FMOs (FMO1-FMO5) were detected. By three of those (FMO1-FMO3) genetic polymorphism was proofed.
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