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Interaction of the anticancer drug lenvatinib with cytochrome P450 subfamily 2C
Srogoň, Jiří ; Dračínská, Helena (advisor) ; Hýsková, Veronika (referee)
Lenvatinib is a multi-targeted kinase inhibitor capable of inhibiting these kinases at nanomolar concentrations. For this reason, it is used as a drug in the treatment of various types of cancer. Like many other xenobiotics, lenvatinib is metabolized by cytochromes P450, which can cause occurrence of drug interactions with other substances. Identification of the most important and clinically relevant drug interactions is essential to ensure the safety of patients already suffering from reduced quality of life due to cancer. The main aim of this bachelor thesis was to investigate the effect of lenvatinib on cytochromes P450, specifically on isoforms of subfamily 2C in humans and rats. The inhibitory effect was measured in vitro using marker rections on rat liver microsome samples for the CYP2C6 isoform and on human recombinant CYP2C9 isoform samples expressed in SuperosomesTM or Bactosomes® . Furthermore, the effect of lenvatinib on CYP2C11 and 2C6 expression in the liver of rats exposed to lenvatinib was investigated. Lenvatinib caused a decrease in the activity of the human recombinant CYP2C9 isoform, whereas no effect was observed on the activity of the CYP2C6 isoform in rat liver microsomes. One of the other objectives was to determine the IC50 for CYP2C9, but the objective was not met. When...
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The effect of antitumor agents on the expression and activity of cytochrome P450 subfamily 2C
Uher, Tomáš ; Dračínská, Helena (advisor) ; Feglarová, Tereza (referee)
Targeted therapies, acting by blocking essential biochemical pathways required for tumor cell growth and survival, are being used lately in multiple cases of cancer treatment. Cabozantinib, a small molecule inhibitor of receptor tyrosine kinases, is an example of a targeted drug, regulating growth, angiogenesis and metastatic pro- gression of medullary thyroid cancer. Such drugs are also often complemented by cytotoxic agents, e.g. ellipticine; however, therapeutic usage of ellipticine itself is limited due to its poor solutibility and variety of adverse effects. In this bachelor thesis, effects of cabozantinib, ellipticine, or their combina- tion on gene and protein expression of cytochromes P450 2C6 and 2C11 have been studied in vivo. Aforementioned cytochromes have an important role in biotrans- formation of xenobiotics in rat liver. Their protein expression has been assessed by Western blot immunoassay technique, while the gene expression was evaluated by quantitative PCR method. Furthermore, the effects of studied substances and their combination on CYP2C6 and CYP2C11 specific activity have been determined by diclofenac 4'-hydroxylation and testosterone 16α-hydroxylation, respectively. Additionally, direct inhibitory effect of cabozantinib on recombinant CYP2C11 rat isoform has been studied in...
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Inhibitory effect of 17α-ethinylestradiol on the activity of cytochrome P450 subfamilies 2B and 2C
Knapp, Kryštof ; Dračínská, Helena (advisor) ; Kukačka, Zdeněk (referee)
17α-ethinylestradiol (EE2) is a synthetic derivative of endogenous estrogen 17β-estradiol. It is widely used in pharmaceutics as a ingredient of female oral contraceptives and also in hormone replacement therapy for women with postmenopausal syndrome. Due to its high estrogenic potential together with resistance to the chemical degradation and tendency to bio- accumulate in environment it is considered as an important persistent organic pollutant. In organisms, EE2 is oxidatively metabolised by enzymes from a family of cyto- hromes P450. Some studies show that EE2 is also a potent inhibitor of some isoforms from cytochrome P450 family. In this work, we studied inhibitory effect of EE2 on two human isoforms CYP2B6, CYP2C9 and their rat orthologs CYP2B1 and 2C6, respectively. All studied isoforms exhibited reduced enzyme activity in the presence of EE2. The greatest decrease of enzyme activity was observed with CYP2B1 catalyzing pentoxyresoru n O-depentylation with value of IC50 = 9,6 µM. For hydroxylation of bupropion, selective reaction of CYP2B1 and CYP2B6, EE2 behaved as a more potent inhibitor of CYP2B6 with IC50 = 60 µM. The inhibitory effect of EE2 on rat CYP2B1 for similar reaction conditions was signi cantly lower. With 200µM concentration of EE2, CYP2B1 exhibited still more than 50 % of...
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