Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b5Activity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62156489%3A43210%2F20%3A43918941" target="_blank" >RIV/62156489:43210/20:43918941 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/20:10420126 RIV/00216305:26620/20:PU139469
Result on the web
<a href="https://doi.org/10.3390/biomedicines8120547" target="_blank" >https://doi.org/10.3390/biomedicines8120547</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/biomedicines8120547" target="_blank" >10.3390/biomedicines8120547</a>
Alternative languages
Result language
angličtina
Original language name
Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b5Activity
Original language description
Herein, the in vitro metabolism of tyrosine kinase inhibitor cabozantinib, the drug used for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma, was studied using hepatic microsomal samples of different human donors, human recombinant cytochromes P450 (CYPs), flavin-containing mono-oxygenases (FMOs) and aldehyde oxidase. After incubation with human microsomes, three metabolites, namely cabozantinib N-oxide, desmethyl cabozantinib and monohydroxy cabozantinib, were detected. Significant correlations were found between CYP3A4 activity and generation of all metabolites. The privileged role of CYP3A4 was further confirmed by examining the effect of CYP inhibitors and by human recombinant enzymes. Only four of all tested human recombinant cytochrome P450 were able to oxidize cabozantinib, and CYP3A4 exhibited the most efficient activity. Importantly, cytochrome b5 (cyt b5) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b5 also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b5 . Since CYP3A4 exhibits high expression in the human liver and was found to be the most efficient enzyme in cabozantinib oxidation, we examined the kinetics of this oxidation. The present study provides substantial insights into the metabolism of cabozantinib and brings novel findings related to cabozantinib pharmacokinetics towards possible utilization in personalized medicine.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
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
Biomedicines
ISSN
2227-9059
e-ISSN
—
Volume of the periodical
8
Issue of the periodical within the volume
12
Country of publishing house
CH - SWITZERLAND
Number of pages
14
Pages from-to
547
UT code for WoS article
000601740700001
EID of the result in the Scopus database
2-s2.0-85097264909