RT Journal Article
SR Electronic
T1 Interactions of Tyrosine Kinase Inhibitors with Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Proteins
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 531
OP 539
DO 10.1158/1535-7163.MCT-10-0731
VO 10
IS 3
A1 Minematsu, Tsuyoshi
A1 Giacomini, Kathleen M.
YR 2011
UL http://mct.aacrjournals.org/content/10/3/531.abstract
AB The drug–drug interaction (DDI) potential of tyrosine kinase inhibitors (TKI) as interacting drugs via transporter inhibition has not been fully assessed. Here, we estimated the half maximal inhibitory concentration (IC50) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on [14C]metformin transport by human organic cation transporters (OCT), OCT1, OCT2, and OCT3, and multidrug and toxic compound extrusion (MATE) proteins, MATE1 and MATE2-K, using human embryonic kidney cells stably expressing these transporters. We then compared the estimated IC50 values to the maximum clinical concentrations of unbound TKIs in plasma (unbound Cmax,sys,p). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound Cmax,sys,p/IC50 values ≥0.1, on MATE1, OCT3, MATE2-K, and OCT1, respectively. In comparison to the common form of OCT1, the OCT1 polymorphism, M420del, was more sensitive to drug inhibition by erlotinib. Major metabolites of several TKIs showed IC50 values similar to those for unchanged TKIs. Taken together, these findings suggest the potential of clinical transporter-mediated DDIs between specific TKIs and OCTs and MATEs, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are substrates of these transporters. The study provides the basis for further clinical DDI studies with TKIs. Mol Cancer Ther; 10(3); 531–9. ©2011 AACR.