title: Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug interaction between pazopanib and cisplatin.
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.
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: C
authors.initials: C
authors.lastname: Sauzay
authors.affiliation: CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: M
authors.initials: M
authors.lastname: White-Koning
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: I
authors.initials: I
authors.lastname: Hennebelle
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: T
authors.initials: T
authors.lastname: Deluche
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: C
authors.initials: C
authors.lastname: Delmas
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: D C
authors.initials: DC
authors.lastname: Imbs
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France.
authors.forename: E
authors.initials: E
authors.lastname: Chatelut
authors.affiliation: Institut Claudius-Regaud, IUCT-O, Department of Pharmacology, Toulouse F-31059, France; CRCT, INSERM UMR1037, Univ. Toulouse III Paul Sabatier-ERL5294 CNRS, Toulouse F-31037, France. Electronic address: thomas.fabienne@iuct-oncopole.fr.
authors.forename: F
authors.initials: F
authors.lastname: Thomas
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D007191:Indazoles; D007700:Kinetics; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism; D011743:Pyrimidines / Q000633:toxicity*; D065667:Renal Elimination / Q000187:drug effects; D013449:Sulfonamides / Q000633:toxicity*; D014162:Transfection
chemical_list: C032315:4-(4-dimethylaminostyryl)-1-methylpyridinium; D020533:Angiogenesis Inhibitors; D007191:Indazoles; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds; D011743:Pyrimidines; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D013449:Sulfonamides; C516667:pazopanib; D002945:Cisplatin
keywords: Cisplatin; Drug-drug interaction; OCT-2; Pazopanib; Renal transporters