The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver
Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the orga...
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| Format: | Article |
| Language: | English |
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Sciendo
2024-09-01
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| Series: | Acta Pharmaceutica |
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| Online Access: | https://doi.org/10.2478/acph-2024-0027 |
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| author | Indra Radek Jelínková Sandra Kollárová Katarína Zahumenská Petra Dvořák Josef Dušková Šárka Dračínská Helena |
| author_facet | Indra Radek Jelínková Sandra Kollárová Katarína Zahumenská Petra Dvořák Josef Dušková Šárka Dračínská Helena |
| author_sort | Indra Radek |
| collection | DOAJ |
| description | Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in SupersomesTM in vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs. |
| format | Article |
| id | doaj-art-889dbc982d354cca8e95610ad1cdb2d3 |
| institution | Kabale University |
| issn | 1846-9558 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Sciendo |
| record_format | Article |
| series | Acta Pharmaceutica |
| spelling | doaj-art-889dbc982d354cca8e95610ad1cdb2d32025-02-02T08:34:38ZengSciendoActa Pharmaceutica1846-95582024-09-0174344145910.2478/acph-2024-0027The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liverIndra Radek0Jelínková Sandra1Kollárová Katarína2Zahumenská Petra3Dvořák Josef4Dušková Šárka5Dračínská Helena6Department of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicDepartment of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicDepartment of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicDepartment of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicDepartment of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicCentre of Occupational Health, National Institute of Public Health, 100 42 Prague 10, Czech RepublicDepartment of Biochemistry, Faculty of Science, Charles University, 128 00 Prague 2, Czech RepublicLenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in SupersomesTM in vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs.https://doi.org/10.2478/acph-2024-0027lenvatinibcytochrome p450tyrosine kinase inhibitorprotein expression |
| spellingShingle | Indra Radek Jelínková Sandra Kollárová Katarína Zahumenská Petra Dvořák Josef Dušková Šárka Dračínská Helena The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver Acta Pharmaceutica lenvatinib cytochrome p450 tyrosine kinase inhibitor protein expression |
| title | The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver |
| title_full | The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver |
| title_fullStr | The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver |
| title_full_unstemmed | The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver |
| title_short | The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver |
| title_sort | tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes p450 and affects their expression in rat liver |
| topic | lenvatinib cytochrome p450 tyrosine kinase inhibitor protein expression |
| url | https://doi.org/10.2478/acph-2024-0027 |
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