Identification of enzymes oxidizing the tyrosine kinase inhibitor cabozantinib: Cabozantinib is predominantly oxidized by CYP3A4 and its oxidation is stimulated by cyt b5 activity

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dc.contributor.authorIndra, Radekcs
dc.contributor.authorVavrová, Katarínacs
dc.contributor.authorPompach, Petrcs
dc.contributor.authorHeger, Zbyněkcs
dc.contributor.authorHodek, Petrcs
dc.coverage.issue12cs
dc.coverage.volume8cs
dc.date.accessioned2021-03-08T15:54:41Z
dc.date.available2021-03-08T15:54:41Z
dc.date.issued2020-12-30cs
dc.description.abstractHerein, 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 b(5) (cyt b(5)) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b(5) also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b(5). 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.en
dc.formattextcs
dc.format.extent1-14cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationBiomedicines. 2020, vol. 8, issue 12, p. 1-14.en
dc.identifier.doi10.3390/biomedicines8120547cs
dc.identifier.issn2227-9059cs
dc.identifier.other169451cs
dc.identifier.urihttp://hdl.handle.net/11012/196448
dc.language.isoencs
dc.publisherMDPIcs
dc.relation.ispartofBiomedicinescs
dc.relation.urihttps://www.mdpi.com/2227-9059/8/12/547cs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/2227-9059/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectcabozantiniben
dc.subjectcytochrome P450en
dc.subjecttyrosine kinase inhibitoren
dc.subjectcytochrome b(5)en
dc.titleIdentification of enzymes oxidizing the tyrosine kinase inhibitor cabozantinib: Cabozantinib is predominantly oxidized by CYP3A4 and its oxidation is stimulated by cyt b5 activityen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-169451en
sync.item.dbtypeVAVen
sync.item.insts2021.03.08 16:54:41en
sync.item.modts2021.03.08 16:14:13en
thesis.grantorVysoké učení technické v Brně. Středoevropský technologický institut VUT. Chytré nanonástrojecs
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