@misc{HofmanSorfVagiannisetal., author = {Hofman, Jakub and Sorf, Ales and Vagiannis, Dimitrios and Sucha, Simona and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Chen, Si and Guo, Lei and Ceckova, Martina and Staud, Frantisek}, title = {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}, series = {Molecular Pharmaceutics}, volume = {16}, journal = {Molecular Pharmaceutics}, number = {11}, doi = {10.1021/acs.molpharmaceut.9b00361}, pages = {4436 -- 4450}, language = {en} } @misc{HofmanSorfVagiannisetal., author = {Hofman, Jakub and Sorf, Ales and Vagiannis, Dimitrios and Sucha, Simona and Novotna, Eva and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Ceckova, Martina and Staud, Frantisek}, title = {Interactions of Alectinib with Human ATP-Binding Cassette Drug Efflux Transporters and Cytochrome P450 Biotransformation Enzymes: Effect on Pharmacokinetic Multidrug Resistance}, series = {Drug Metabolism and Disposition}, volume = {47}, journal = {Drug Metabolism and Disposition}, number = {7}, issn = {1521-009X}, doi = {10.1124/dmd.119.086975}, pages = {699 -- 709}, language = {en} } @misc{VagiannisNovotnaSkarkaetal., author = {Vagiannis, Dimitrios and Novotna, Eva and Skarka, Adam and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Chen, Si and Guo, Lei and Staud, Frantisek and Hofman, Jakub}, title = {Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers12040813}, pages = {27}, abstract = {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.}, language = {en} }