Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug interaction between pazopanib and cisplatin. (August 2016)

• Record Type: Journal Article
• Authors: Sauzay, C.; White-Koning, M.; Hennebelle, I.; Deluche, T.; Delmas, C.; Imbs, D.C.; Chatelut, E.; Thomas, F.
• Is Part Of: Pharmacological research. Volume 110(2016:Aug.)
• Page Start: 89
• Page End: 95
• Publication Date: 2016-08
• Subjects: OCT2 organic cation transporter 2 -- MATE multidrug and toxin extrusion -- OATP organic anion transporting polypeptide -- TKI tyrosine kinase inhibitors -- EV empty vector -- ASP+ 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide -- DDI drug–drug interaction -- VEGFR vascular endothelial growth factor receptor -- PDGFR platelet-derived growth factor receptor -- ABCB1 ATP-binding cassette sub-family B member 1 -- ABCG2 ATP-binding cassette protein G2 -- CYP cytochrome P450 -- Km Michaelis-Menten constant -- RIPA radioimmunoprecipitation assay -- HBSS Hank's Balanced Salt Solution -- DMF N, N-diméthylformamide -- BCA bicinchoninic acid -- Cmax maximal plasma concentration; Cisplatin -- Pazopanib -- Renal transporters -- OCT-2 -- Drug-drug interaction; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.05.012
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: We hypothesized that pazopanib is an inhibitor of cisplatin renal transporters OCT2, MATE1 and MATE2-K based on previous studies demonstrating an interaction between tyrosine kinase inhibitors and these transporters. Because several combinations of targeted therapies and cytotoxics are currently in development for cancer treatment, such an interaction is worth investigating. Experiments on HEK293 cells stably transfected to express OCT2, MATE1, MATE2-K or an empty vector (EV) were conducted. The inhibitory effect of pazopanib on these transporters was measured using the uptake of fluorescent substrate ASP+ and cisplatin in the different cell lines. The effect of pazopanib on cisplatin-induced cytotoxicity was also evaluated. A decrease of ASP+ uptake was observed in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines after addition of pazopanib at increasing concentrations. Pazopanib inhibited cisplatin specific uptake in OCT2-HEK, MATE1-HEK and MATE2K-HEK lines. Cytotoxicity experiments showed that co-incubation of cisplatin with pazopanib multiplied up to 2.7, 2.4 and 1.6 times the EC50 values of cisplatin in OCT2-HEK, MATE1-HEK and MATE2K-HEK cell lines respectively, reaching about the same values as in EV-HEK cells. To conclude, pazopanib inhibits OCT2, MATE1 and MATE2-K, which are involved in cisplatin secretion into urine. The combination of these two drugs may lead to an interaction and increase the cisplatin-induced systemic toxicity. Given the wide variability of plasma pazopanib concentrations observed in vivo, the interaction may occur in a clinical setting, particularly in overexposed patients. The existence of a drug–drug interaction should be investigated when pazopanib is associated with a substrate of these transporters.