1. Academic Validation
  2. The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib

The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib

  • Biomed Pharmacother. 2022 Jan;145:112391. doi: 10.1016/j.biopha.2021.112391.
Katarína Vavrová 1 Radek Indra 2 Petr Pompach 1 Zbyněk Heger 3 Petr Hodek 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 128 00 Prague 2, Czech Republic.
  • 2 Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 128 00 Prague 2, Czech Republic. Electronic address: radek.indra@natur.cuni.cz.
  • 3 Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic; Central European Institute of Technology, Brno University of Technology, Purkynova 656/123, 612 00 Brno, Czech Republic.
Abstract

Lenvatinib, a small molecule tyrosine kinase inhibitor (TKI), exhibits good inhibitory effect in several types of carcinomas. Specifically, it is the most effective TKI used for treatment of thyroid Cancer. To extend pharmacokinetics data on this Anticancer agent, we aimed to identify the metabolites of lenvatinib formed during in vitro incubation of lenvatinib with human hepatic microsomes or recombinant cytochromes P450 (CYPs) by using high performance liquid chromatography and mass spectrometry. The role of CYPs in the oxidation of lenvatinib was initially investigated in hepatic microsomes using specific CYP inhibitors. CYP-catalytic activities in each microsomal sample were correlated with the amounts of lenvatinib metabolites formed by these samples. Further, human recombinant CYPs were employed in the metabolic studies. Based on our data, lenvatinib is metabolized to O-desmethyl lenvatinib, N-descyclopropyl lenvatinib and lenvatinib N-oxide. In the presence of cytochrome b5, recombinant CYP3A4 was the most efficient to form these metabolites. In addition, CYP1A1 significantly contributes to the lenvatinib metabolism. It was even more efficient in forming of O-desmethyl lenvatinib than CYP3A4 in the absence of cytochrome b5. The present study indicates that further research focused on drug-drug interactions, in particular on CYP3A4 and CYP1A1 modulators, is needed. This will pave new avenues towards TKIs-mediated personalized therapy.

Keywords

Cytochrome P450; Lenvatinib; Metabolism; Tyrosine kinase inhibitor.

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