Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216305%3A26620%2F18%3APU136048" target="_blank" >RIV/00216305:26620/18:PU136048 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1002/2211-5463.12453" target="_blank" >https://doi.org/10.1002/2211-5463.12453</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine

Popis výsledku v původním jazyce

Vandetanib is a tyrosine kinase inhibitor (TKI) used for treatment of certain tumors of the thyroid gland. It inhibits signalling of epidermal growth, vascular endothelial growth factor or rearranged during transfection. Here, using human hepatic microsomes and recombinant cytochromes P450 (CYPs) and flavincontaining monooxygenases (FMOs) expressed in Supersomes TM, oxidation of vandetanib was studied. The vandetanib metabolites were separated by HPLC and identified by mass spectroscopy. Human hepatic microsomes oxidize vandetanib to N-desmethyl-vandetanib, but not to vandetanib-N-oxide. Of all tested human CYP enzymes, the CYP1A1, 2C8, 2D6, 3A4 and 3A5 enzymes, mainly in the presence of cytochrome b5, oxidize vandetanib to N-desmethylvandetanib. No vandetanib-N-oxide was generated by tested human CYPs. However, FMO enzymes were able to generate this metabolite. Of three human FMOs tested (FMO1, FMO3 and FMO5), FMO1 and FMO3 oxidize vandetanib to vandetanib-N-oxide. FMO1 was more effective than FMO3

Název v anglickém jazyce

Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine

Popis výsledku anglicky

Vandetanib is a tyrosine kinase inhibitor (TKI) used for treatment of certain tumors of the thyroid gland. It inhibits signalling of epidermal growth, vascular endothelial growth factor or rearranged during transfection. Here, using human hepatic microsomes and recombinant cytochromes P450 (CYPs) and flavincontaining monooxygenases (FMOs) expressed in Supersomes TM, oxidation of vandetanib was studied. The vandetanib metabolites were separated by HPLC and identified by mass spectroscopy. Human hepatic microsomes oxidize vandetanib to N-desmethyl-vandetanib, but not to vandetanib-N-oxide. Of all tested human CYP enzymes, the CYP1A1, 2C8, 2D6, 3A4 and 3A5 enzymes, mainly in the presence of cytochrome b5, oxidize vandetanib to N-desmethylvandetanib. No vandetanib-N-oxide was generated by tested human CYPs. However, FMO enzymes were able to generate this metabolite. Of three human FMOs tested (FMO1, FMO3 and FMO5), FMO1 and FMO3 oxidize vandetanib to vandetanib-N-oxide. FMO1 was more effective than FMO3

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů