TY - GEN A1 - Hofman, Jakub A1 - Sorf, Ales A1 - Vagiannis, Dimitrios A1 - Sucha, Simona A1 - Kammerer, Sarah A1 - Küpper, Jan-Heiner A1 - Chen, Si A1 - Guo, Lei A1 - Ceckova, Martina A1 - Staud, Frantisek T1 - Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes T2 - Molecular Pharmaceutics Y1 - 2019 U6 - https://doi.org/10.1021/acs.molpharmaceut.9b00361 VL - 16 IS - 11 SP - 4436 EP - 4450 ER - TY - GEN A1 - Hofman, Jakub A1 - Sorf, Ales A1 - Vagiannis, Dimitrios A1 - Sucha, Simona A1 - Novotna, Eva A1 - Kammerer, Sarah A1 - Küpper, Jan-Heiner A1 - Ceckova, Martina A1 - Staud, Frantisek T1 - Interactions of Alectinib with Human ATP-Binding Cassette Drug Efflux Transporters and Cytochrome P450 Biotransformation Enzymes: Effect on Pharmacokinetic Multidrug Resistance T2 - Drug Metabolism and Disposition Y1 - 2019 U6 - https://doi.org/10.1124/dmd.119.086975 SN - 1521-009X SN - 0090-9556 VL - 47 IS - 7 SP - 699 EP - 709 ER - TY - GEN A1 - Vagiannis, Dimitrios A1 - Novotna, Eva A1 - Skarka, Adam A1 - Kammerer, Sarah A1 - Küpper, Jan-Heiner A1 - Chen, Si A1 - Guo, Lei A1 - Staud, Frantisek A1 - Hofman, Jakub T1 - Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme T2 - Cancers N2 - Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib’s antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations. KW - ensartinib KW - cancer KW - multidrug resistance KW - drug-drug interaction KW - ABC transporter KW - cytochrome P450 Y1 - 2020 UR - https://www.mdpi.com/2072-6694/12/4/813 U6 - https://doi.org/10.3390/cancers12040813 SN - 2072-6694 VL - 12 IS - 4 ER -