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Study of metabolism of tyrosine kinase inhibitors and mechanism of their anticancer effects
Vavrová, Katarína
As inhibitors of tyrosine kinases have become more widely used in anticancer therapy, detailed understanding of their pharmacokinetic profile is increasingly essential for the improvement of treatment outcomes. Herein, the metabolism in liver microsomes in animal models and humans was studied. Clarification of which liver enzymes, specifically cytochromes P450 (CYP), are involved in the metabolism of vandetanib, cabozantinib and, lenvatinib, may play a key role in oncology practice, as these anticancer drugs are administrated in combination with other drugs. This co-administration may pose a risk of drug interactions, which may result in decreased efficacy or increased drug-related toxicity. To elucidate the metabolism of our selected anticancer drugs in human liver, the same approaches were gradually used- correlation analysis using human liver microsomes from 12 different donors, inhibition studies, and the use of recombinant CYP. In addition, an approach with animal liver microsomes that were premedicated with inducers of individual CYP was used to elucidate vandetanib metabolism in rat liver. Our first studied tyrosine kinase inhibitor was vandetanib. In the first paper, we studied its metabolism in humans through various approaches, and subsequently in another publication in rat. The...
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Study of metabolism of tyrosine kinase inhibitors and mechanism of their anticancer effects
Vavrová, Katarína ; Indra, Radek (advisor) ; Souček, Pavel (referee) ; Ječmen, Tomáš (referee)
As inhibitors of tyrosine kinases have become more widely used in anticancer therapy, detailed understanding of their pharmacokinetic profile is increasingly essential for the improvement of treatment outcomes. Herein, the metabolism in liver microsomes in animal models and humans was studied. Clarification of which liver enzymes, specifically cytochromes P450 (CYP), are involved in the metabolism of vandetanib, cabozantinib and, lenvatinib, may play a key role in oncology practice, as these anticancer drugs are administrated in combination with other drugs. This co-administration may pose a risk of drug interactions, which may result in decreased efficacy or increased drug-related toxicity. To elucidate the metabolism of our selected anticancer drugs in human liver, the same approaches were gradually used- correlation analysis using human liver microsomes from 12 different donors, inhibition studies, and the use of recombinant CYP. In addition, an approach with animal liver microsomes that were premedicated with inducers of individual CYP was used to elucidate vandetanib metabolism in rat liver. Our first studied tyrosine kinase inhibitor was vandetanib. In the first paper, we studied its metabolism in humans through various approaches, and subsequently in another publication in rat. The...
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Metabolism of an inhibitor of tyrosine kinase lenvatinib as the anticancer drug with targeting effects
Vavrová, Katarína ; Stiborová, Marie (advisor) ; Kubíčková, Božena (referee)
Lenvatinib is an oral anticancer drug that belongs to a group of tyrosine kinases, which block signal pathway receptors for development and proliferation of various cancer diseases. Lenvatinib was approved in 2015 for a treatment of progressive, locally spread or metastatic, differentiated thyroid cancer refractory to radioiodine treatment. This thesis presents findings about the metabolism of lenvatinib and identification of enzymes responsible for biotransformation of this drug. Utilizing human and rat hepatic microsomes as well as recombinant cytochromes P450 (CYPs) expressed in SupersomesTM , the metabolism of lenvatinib was studied. Used rat microsomal systems were isolated from the liver of uninduced rats and from the liver of rats in which expression of individual CYPs was induced by CYP inducers. The lenvatinib metabolites were separated by HPLC and identified by mass spectroscopy. Using rat microsomal systems, O-desmethyllenvatinib and lenvatinib N-oxide were produced. The highest amount of these lenvatinib metabolites was produced by microsomes of rats pretreated with pregnenolone carbonitrile that is an inducer of CYP3A. Human hepatic microsomes oxidize lenvatinib to O-desmethyllenvatinib and N-descyklopropyllenvatinib. In the case of rat recombinant CYPs, O-desmethyllenvatinib was...
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