Talazoparib (Talzenna) is a novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is clinically used for the therapy of breast cancer. Furthermore, the drug has shown antitumor activity against different cancer types, including non-small cell lung cancer (NSCLC). In this work, we investigated the possible inhibitory interactions of talazoparib toward selected ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs) and evaluated its position in multidrug resistance (MDR). In accumulation studies, talazoparib interacted with the ABCC1 and ABCG2 transporters, but there were no significant effects on ABCB1. Furthermore, incubation assays revealed a negligible capacity of the tested drug to inhibit clinically relevant CYPs. In in vitro drug combination experiments, talazoparib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCC1 and ABCG2 expression, respectively. Importantly, the position of an effective MDR modulator was further confirmed in drug combinations performed in ex vivo NSCLC patients-derived explants, whereas the possible victim role was refuted in comparative proliferation experiments. In addition, talazoparib had no significant effects on the mRNA-level expressions of MDR-related ABC transporters in the MCF-7 cellular model. In summary, our study presents a comprehensive overview on the pharmacokinetic drug-drug interactions (DDI) profile of talazoparib. Moreover, we introduced talazoparib as an efficient MDR antagonist.

• Keywords
• ABC transporter, cytochrome P450, multidrug resistance, pharmacokinetic drug–drug interaction, small cell lung cancer, talazoparib,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   MeSH
• ATP-Binding Cassette Transporters genetics   metabolism   MeSH
• Humans MeSH
• Drug Resistance, Multiple MeSH
• Neoplasm Proteins metabolism   MeSH
• Lung Neoplasms * MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   genetics   MeSH
• ATP Binding Cassette Transporter, Subfamily B genetics   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ATP-Binding Cassette Transporters MeSH
• ABCB1 protein, human MeSH Browser
• ABCG2 protein, human MeSH Browser
• Neoplasm Proteins MeSH
• ATP Binding Cassette Transporter, Subfamily B MeSH
• Cytochrome P-450 Enzyme System MeSH
• talazoparib MeSH Browser

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.

• Keywords
• ABC transporter, cytochrome P450, drug interaction, multidrug resistance, non-small cell lung cancer, tepotinib,
• MeSH
• ATP-Binding Cassette Transporters antagonists & inhibitors   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Cytostatic Agents pharmacology   MeSH
• Drug Interactions * MeSH
• Humans MeSH
• Drug Resistance, Multiple drug effects   MeSH
• Lung Neoplasms drug therapy   metabolism   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung drug therapy   metabolism   pathology   MeSH
• Piperidines pharmacology   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Pyridazines pharmacology   MeSH
• Pyrimidines pharmacology   MeSH
• In Vitro Techniques MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP-Binding Cassette Transporters MeSH
• Cytostatic Agents MeSH
• Piperidines MeSH
• Antineoplastic Agents MeSH
• Pyridazines MeSH
• Pyrimidines MeSH
• tepotinib MeSH Browser

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.

• Keywords
• ABC transporter, cancer, cytochrome P450, drug-drug interaction, ensartinib, multidrug resistance,
• Publication type
• Journal Article 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.

• Keywords
• NBMPR, breast cancer resistance protein, equilibrative nucleoside transporters, inhibition, selectivity,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors   metabolism   MeSH
• Antiviral Agents metabolism   pharmacokinetics   MeSH
• Biological Transport drug effects   MeSH
• Cell Line MeSH
• Madin Darby Canine Kidney Cells MeSH
• Rats MeSH
• Humans MeSH
• Neoplasm Proteins antagonists & inhibitors   metabolism   MeSH
• ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors   metabolism   MeSH
• Placenta drug effects   metabolism   MeSH
• Rats, Wistar MeSH
• Dogs MeSH
• Pregnancy MeSH
• Thioinosine analogs & derivatives   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Dogs MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-nitrobenzylthioinosine MeSH Browser
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ABCB1 protein, human MeSH Browser
• ABCG2 protein, human MeSH Browser
• Antiviral Agents MeSH
• Neoplasm Proteins MeSH
• ATP Binding Cassette Transporter, Subfamily B MeSH
• Thioinosine MeSH