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

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 metabolite...

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Autores principales:	Katarína Vavrová, Radek Indra, Petr Pompach, Zbyněk Heger, Petr Hodek
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Lenvatinib Tyrosine kinase inhibitor Metabolism Cytochrome P450 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/2f244a7545cb4a5faf7f44487ac55988
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spelling	oai:doaj.org-article:2f244a7545cb4a5faf7f44487ac559882021-11-28T04:28:07ZThe impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib0753-332210.1016/j.biopha.2021.112391https://doaj.org/article/2f244a7545cb4a5faf7f44487ac559882022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S075333222101177Xhttps://doaj.org/toc/0753-3322Lenvatinib, 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.Katarína VavrováRadek IndraPetr PompachZbyněk HegerPetr HodekElsevierarticleLenvatinibTyrosine kinase inhibitorMetabolismCytochrome P450Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112391- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lenvatinib Tyrosine kinase inhibitor Metabolism Cytochrome P450 Therapeutics. Pharmacology RM1-950
spellingShingle	Lenvatinib Tyrosine kinase inhibitor Metabolism Cytochrome P450 Therapeutics. Pharmacology RM1-950 Katarína Vavrová Radek Indra Petr Pompach Zbyněk Heger Petr Hodek The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
description	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.
format	article
author	Katarína Vavrová Radek Indra Petr Pompach Zbyněk Heger Petr Hodek
author_facet	Katarína Vavrová Radek Indra Petr Pompach Zbyněk Heger Petr Hodek
author_sort	Katarína Vavrová
title	The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
title_short	The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
title_full	The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
title_fullStr	The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
title_full_unstemmed	The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib
title_sort	impact of individual human cytochrome p450 enzymes on oxidative metabolism of anticancer drug lenvatinib
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/2f244a7545cb4a5faf7f44487ac55988
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The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib

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