Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins

Abstract

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.

Conflict of interest statement

Potential conflicts of interest: No potential conflicts of interest

©2011 AACR.

Figures

Figure 1. Unbound [I]/IC50 values for tyrosine kinase inhibitors as inhibitors of human OCT1, OCT2, OCT3, MATE1, and MATE2-K

Unbound Cmax,sys,p values representing [I], shown in Supplementary Table S1 and IC50 values from Supplementary Table S2 were used in to calculate [I]/IC50. The broken line represents [I]/IC50 = 0.1.

Figure 2. Inhibitory effects of erlotinib on the uptake of [14C]metformin (10 μM for 5 min) by human OCT1 reference and variant (M420del)

Closed symbols represent the uptake of metformin into HEK-hOCT1 reference and HEK-hOCT1 M420del, and open symbols represent the uptake into HEK-MOCK cells. Data are expressed as mean ± SD (n=3).

Figure 3. The effect of preincubation on the inhibitory effects of erlotinib on the uptake of [14C]metformin (10 μM for 5 min) by human OCT1

Closed symbols represent the uptake of metformin into HEK-hOCT1, and open symbols represent the uptake into HEK-MOCK cells. Data are expressed as mean ± SD (n=3).

Figure 4. Interspecies differences in the inhibition potencies (IC50 values) for imatinib, nilotinib, and erlotinib between human and mouse orthologs of OCT1-3, and MATE1

aThe actual IC50 value was estimated to be >50 μM for mouse MATE1. bThe actual IC50 value was estimated to be >30 μM for mouse OCT2 and MATE1 and human OCT2. A solid line represents the line of the unity.

Figure 5. Cellular platinum uptake into HEK-hOCT1, -hOCT2, and -hOCT3 after 2-h incubation with oxaliplatin (2 μM) in the absence and presence of erlotinib and nilotinib

The results are expressed as transporter-specific uptake, subtracting the uptake into HEK-hOCT1, -hOCT2, and -hOCT3 by that into HEK-MOCK. Data are expressed as mean ± SD (n=3).

Figure 6. Correlation between physicochemical properties of TKIs and negative log10(IC50) for human OCT1, OCT2 and MATE1

Pearson's R and P values were calculated (nsP≥0.05, *P<0.05, and ***P<0.001).