Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo.
Article Details
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Vagiannis D, Budagaga Y, Morell A, Zhang Y, Novotna E, Skarka A, Kammerer S, Kupper JH, Hanke I, Rozkos T, Hofman J
Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo.
Int J Mol Sci. 2021 Nov 3;22(21). pii: ijms222111936. doi: 10.3390/ijms222111936.
- PubMed ID
- 34769363 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Tepotinib Cytochrome P450 2C9 Protein Humans NoInhibitorDetails Tepotinib Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Tepotinib Bile salt export pump Protein Humans NoInhibitorDetails