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.

• Klíčová slova
• ABC transporter, cytochrome P450, drug interaction, multidrug resistance, non-small cell lung cancer, tepotinib,
• MeSH
• ABC transportéry antagonisté a inhibitory   MeSH
• chemorezistence účinky léků   MeSH
• cytostatické látky farmakologie   MeSH
• lékové interakce * MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• nádory plic farmakoterapie   metabolismus   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   metabolismus   patologie   MeSH
• piperidiny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• pyridaziny farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• cytostatické látky MeSH
• piperidiny MeSH
• protinádorové látky MeSH
• pyridaziny MeSH
• pyrimidiny MeSH
• tepotinib MeSH Prohlížeč

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.

• Klíčová slova
• ABC transporter, cancer, cytochrome P450, drug-drug interaction, ensartinib, multidrug resistance,
• Publikační typ
• časopisecké články MeSH

PURPOSE: S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 μM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of [3H]zidovudine and [3H]tenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2). METHODS: We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate [3H]glyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and in situ dual perfusions of rat term placenta with glyburide. RESULTS: NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC50 = 53 μM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional [3H]glyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated [3H]glyburide efflux by rat term placenta in situ. CONCLUSION: NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.

• Klíčová slova
• NBMPR, breast cancer resistance protein, equilibrative nucleoside transporters, inhibition, selectivity,
• MeSH
• ABC transportér z rodiny G, člen 2 antagonisté a inhibitory   metabolismus   MeSH
• antivirové látky metabolismus   farmakokinetika   MeSH
• biologický transport účinky léků   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• P-glykoproteiny antagonisté a inhibitory   metabolismus   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• psi MeSH
• těhotenství MeSH
• thioinosin analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 4-nitrobenzylthioinosine MeSH Prohlížeč
• ABC transportér z rodiny G, člen 2 MeSH
• ABCB1 protein, human MeSH Prohlížeč
• ABCG2 protein, human MeSH Prohlížeč
• antivirové látky MeSH
• nádorové proteiny MeSH
• P-glykoproteiny MeSH
• thioinosin MeSH

Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport fyziologie   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• krysa rodu Rattus MeSH
• lamivudin metabolismus   MeSH
• lidé MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• psi MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCC2 protein, human MeSH Prohlížeč
• lamivudin MeSH
• P-glykoproteiny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH