Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins.
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 (IC(50)) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on [(14)C]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 IC(50) values to the maximum clinical concentrations of unbound TKIs in plasma (unbound C(max,sys,p)). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound C(max,sys,p)/IC(50) 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 IC(50) 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.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA.
Tsuyoshi
T
Minematsu
Kathleen M
KM
Giacomini
D001692:Biological Transport; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D027701:Organic Cation Transport Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D011505:Protein-Tyrosine Kinases
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