Detail publikace

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

VAVROVÁ, K. INDRA, R. POMPACH, P. HEGER, Z. HODEK, P.

Originální název

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

Typ

článek v časopise ve Web of Science, Jimp

Jazyk

angličtina

Originální abstrakt

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.

Klíčová slova

Lenvatinib; Tyrosine kinase inhibitor; Metabolism; Cytochrome P450

Autoři

VAVROVÁ, K.; INDRA, R.; POMPACH, P.; HEGER, Z.; HODEK, P.

Vydáno

1. 1. 2022

Nakladatel

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Místo

ISSY-LES-MOULINEAUX

ISSN

1950-6007

Periodikum

BIOMEDICINE & PHARMACOTHERAPY

Ročník

145

Číslo

112391

Stát

Francouzská republika

Strany počet

10

URL

https://www.sciencedirect.com/science/article/pii/S075333222101177X?via%3Dihub

BibTex

@article{BUT182246,
  author="Katarína {Vavrová} and Radek {Indra} and Petr {Pompach} and Zbyněk {Heger} and Petr {Hodek}",
  title="The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib",
  journal="BIOMEDICINE & PHARMACOTHERAPY",
  year="2022",
  volume="145",
  number="112391",
  pages="10",
  doi="10.1016/j.biopha.2021.112391",
  issn="1950-6007",
  url="https://www.sciencedirect.com/science/article/pii/S075333222101177X?via%3Dihub"
}