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Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that te...

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Autores principales: Vagiannis, Dimitrios, Budagaga, Youssif, Morell, Anselm, Zhang, Yu, Novotná, Eva, Skarka, Adam, Kammerer, Sarah, Küpper, Jan-Heiner, Hanke, Ivo, Rozkoš, Tomáš, Hofman, Jakub
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584989/
https://www.ncbi.nlm.nih.gov/pubmed/34769363
http://dx.doi.org/10.3390/ijms222111936
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author Vagiannis, Dimitrios
Budagaga, Youssif
Morell, Anselm
Zhang, Yu
Novotná, Eva
Skarka, Adam
Kammerer, Sarah
Küpper, Jan-Heiner
Hanke, Ivo
Rozkoš, Tomáš
Hofman, Jakub
author_facet Vagiannis, Dimitrios
Budagaga, Youssif
Morell, Anselm
Zhang, Yu
Novotná, Eva
Skarka, Adam
Kammerer, Sarah
Küpper, Jan-Heiner
Hanke, Ivo
Rozkoš, Tomáš
Hofman, Jakub
author_sort Vagiannis, Dimitrios
collection PubMed
description Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.
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spelling pubmed-85849892021-11-12 Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo Vagiannis, Dimitrios Budagaga, Youssif Morell, Anselm Zhang, Yu Novotná, Eva Skarka, Adam Kammerer, Sarah Küpper, Jan-Heiner Hanke, Ivo Rozkoš, Tomáš Hofman, Jakub Int J Mol Sci Article Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations. MDPI 2021-11-03 /pmc/articles/PMC8584989/ /pubmed/34769363 http://dx.doi.org/10.3390/ijms222111936 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vagiannis, Dimitrios
Budagaga, Youssif
Morell, Anselm
Zhang, Yu
Novotná, Eva
Skarka, Adam
Kammerer, Sarah
Küpper, Jan-Heiner
Hanke, Ivo
Rozkoš, Tomáš
Hofman, Jakub
Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_full Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_fullStr Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_full_unstemmed Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_short Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_sort tepotinib inhibits several drug efflux transporters and biotransformation enzymes: the role in drug-drug interactions and targeting cytostatic resistance in vitro and ex vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584989/
https://www.ncbi.nlm.nih.gov/pubmed/34769363
http://dx.doi.org/10.3390/ijms222111936
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