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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11936 |
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| author | Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman |
| author_facet | Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman |
| author_sort | Dimitrios Vagiannis |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:00:18Z |
| format | Article |
| id | doaj.art-0212eb51dc624676ad5bb0e9e6facdd1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:00:18Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0212eb51dc624676ad5bb0e9e6facdd12023-11-22T21:00:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122211193610.3390/ijms222111936Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex VivoDimitrios Vagiannis0Youssif Budagaga1Anselm Morell2Yu Zhang3Eva Novotná4Adam Skarka5Sarah Kammerer6Jan-Heiner Küpper7Ivo Hanke8Tomáš Rozkoš9Jakub Hofman10Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradecká 1285, 500 03 Hradec Králové, Czech RepublicInstitute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz 1, 01968 Senftenberg, GermanyInstitute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz 1, 01968 Senftenberg, GermanyDepartment of Cardiac Surgery, Faculty of Medicine, Charles University and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech RepublicThe Fingerland Department of Pathology, Faculty of Medicine, Charles University and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicTepotinib 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.https://www.mdpi.com/1422-0067/22/21/11936tepotinibnon-small cell lung cancermultidrug resistancedrug interactionABC transportercytochrome P450 |
| spellingShingle | Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo International Journal of Molecular Sciences tepotinib non-small cell lung cancer multidrug resistance drug interaction ABC transporter cytochrome P450 |
| 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 | tepotinib non-small cell lung cancer multidrug resistance drug interaction ABC transporter cytochrome P450 |
| url | https://www.mdpi.com/1422-0067/22/21/11936 |
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