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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

D. Vagiannis, Y. Budagaga, A. Morell, Y. Zhang, E. Novotná, A. Skarka, S. Kammerer, JH. Küpper, I. Hanke, T. Rozkoš, J. Hofman

. 2021 ; 22 (21) : . [pub] 20211103

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22003240

Grant support
20-20414Y Czech Science Foundation
334120/C Grant Agency of Charles University
102121/C Grant Agency of Charles University
SVV/2021/260 549 Charles University
Faculty of Science, VT2019-2021 University of Hradec Králové
85009748 European Funds for Regional Development

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.

References provided by Crossref.org

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