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Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62156489%3A43210%2F20%3A43917139" target="_blank" >RIV/62156489:43210/20:43917139 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11310/20:10410840 RIV/00216208:11130/20:10410840 RIV/00064203:_____/20:10410840

  • Result on the web

    <a href="https://doi.org/10.1016/j.etap.2019.103310" target="_blank" >https://doi.org/10.1016/j.etap.2019.103310</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.etap.2019.103310" target="_blank" >10.1016/j.etap.2019.103310</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

  • Original language description

    We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 &gt; &gt;3A1 &gt; 3A2 &gt; 1A1 &gt; 1A2 &gt; 2D1 &gt; 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30104 - Pharmacology and pharmacy

Result continuities

  • Project

    <a href="/en/project/GA18-10251S" target="_blank" >GA18-10251S: Comprehensive insight into mechanisms of action and metabolism of tyrosine kinase inhibitors and a study of ways increasing their antitumor efficiency</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2020

  • Confidentiality

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

Data specific for result type

  • Name of the periodical

    Environmental Toxicology and Pharmacology

  • ISSN

    1382-6689

  • e-ISSN

  • Volume of the periodical

    74

  • Issue of the periodical within the volume

    February

  • Country of publishing house

    NL - THE KINGDOM OF THE NETHERLANDS

  • Number of pages

    9

  • Pages from-to

    103310

  • UT code for WoS article

    000514007200014

  • EID of the result in the Scopus database

    2-s2.0-85076172640