Publication detail

A tyrosine kinase inhibitor lenvatinib is oxidized by human cytochromes P450 and aldehyde oxidase in vitro

VÁVROVÁ, K. INDRA, R. POMPACH, P. HEGER, Z. ADAM, V. ECKSCHLAGER, T. KOPEČKOVÁ, K. STIBOROVÁ, M.

Original Title

A tyrosine kinase inhibitor lenvatinib is oxidized by human cytochromes P450 and aldehyde oxidase in vitro

Type

presentation, poster

Language

English

Original Abstract

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR1-VEGFR3), fibroblast growth factor receptors (FGFR1-FGFR4), platelet-derived growth factor receptor (PDGFR) a, rearranged during transfection (RET), and v-kit (KIT) signalling networks implicated in tumor angiogenesis. It is used for treatment of certain tumors of the thyroid gland and metastatic renal cell carcinoma. Based on preliminary studies using human hepatic microsomes, lenvatinib was suggested to be oxidized by cytochromes P450 (CYPs), mainly by CYP3A4, to its O-demethylated metabolite, a desmethylated form of lenvatinib. However, no direct prove of this suggestion was demonstrated. Therefore, the aim of this study was to investigate the metabolism of lenvatinib by human microsomal enzymes in vitro in detail. Utilizing human hepatic microsomes and recombinant CYPs expressed in Supersomes TM, the metabolism of lenvatinib was studied. The lenvatinib metabolites were separated by HPLC and identified by mass spectroscopy. Using human hepatic microsomes O-desmethyllen-vatinib, N-depropylated lenvatinib and next one metabolite were produced. Of all tested human CYP enzymes, the CYP1A1, 1A2, 2C19 and 3A4 oxidize lenvatinib to several metabolites. O-des-methylated lenvatinib was generated by CYP1A1, 1A2 and 3A4, while CYP2C19 forms another metabolite; its structure has not yet been identified. CYP1A1 and 3A4 are also responsible for oxidation of lenvatinib to N-depropylated metabolite. Cytochrome b5 plays an essential role in the CYP2C19 and 3A4 activities to oxidize lenvatinib. Besides CYPs, aldehyde oxidase (AO) oxidizes lenvatinib forming one metabolite; its structure has not yet been identified. Further characterization of structures of all lenvatinib metabolites formed by the tested enzymatic systems is under way in our laboratory.

Keywords

Lenvatinib; treatment; tumors

Authors

VÁVROVÁ, K.; INDRA, R.; POMPACH, P.; HEGER, Z.; ADAM, V.; ECKSCHLAGER, T.; KOPEČKOVÁ, K.; STIBOROVÁ, M.

Released

31. 7. 2018

Pages from

351

Pages to

351

Pages count

1

URL

https://doi.org/10.1002/2211-5463.12453

BibTex

@misc{BUT163382,
  author="VÁVROVÁ, K. and INDRA, R. and POMPACH, P. and HEGER, Z. and ADAM, V. and ECKSCHLAGER, T. and KOPEČKOVÁ, K. and STIBOROVÁ, M.",
  title="A tyrosine kinase inhibitor lenvatinib is oxidized by human cytochromes P450 and aldehyde oxidase in vitro",
  year="2018",
  pages="351--351",
  url="https://doi.org/10.1002/2211-5463.12453",
  note="presentation, poster"
}