Interactions of Tyrosine Kinase Inhibitors with Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Proteins

Inhibitory effects of erlotinib on the uptake of [¹⁴C]metformin (10 μmol/L for 5 minutes) 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).

The effect of preincubation on the inhibitory effects of erlotinib on the uptake of [¹⁴C]metformin (10 μmol/L for 5 minutes) 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).

Interspecies differences in the inhibition potencies (IC₅₀ values) for imatinib, nilotinib, and erlotinib between human and mouse orthologs of OCT1-3, and MATE1. a, the actual IC₅₀ value was estimated to be >50 μmol/L for mouse MATE1. b, the actual IC₅₀ value was estimated to be >30 μmol/L for mouse OCT2 and MATE1 and human OCT2. A solid line represents the line of the unity.

Cellular platinum uptake into HEK-hOCT1, -hOCT2, and -hOCT3 after 2-hour incubation with oxaliplatin (2 μmol/L) 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).