Implications of interactions between tyrosine kinase inhibitors and human solute carriers in cancer therapy

Abstract

Members of the solute carrier (SLC) family of transporters govern the cellular influx of a multitude of endogenous compounds, xenobiotics and drugs. SLCs including organic anion transporting polypeptide (OATP) 1A2 (SLCO1A2), OATP1B3 (SLCO1B3) and organic cation transporter (OCT) 1 (SLC22A1) participate in the disposition of several anticancer drugs, such as the tyrosine kinase inhibitor (TKI) imatinib. Some of these agents may elicit drug-drug interactions (DDIs) during therapy, so the accumulation of pharmacokinetic data concerning TKIs is of clinical interest. In this project, the impact of TKIs on the uptake of model substrates in cells overexpressing SLC transporters was evaluated. Human embryonic kidney 293 (HEK293) cells were transfected with complementary DNA to express transport proteins. TKIs (10 μM) were then tested for their capacity to inhibit the uptake of a specific transporter-mediated radiolabelled substrate into these cells. Half maximal inhibitory concentrations (IC50) and inhibition constants (Ki) of potent inhibitors were determined. Of the 13 clinically relevant TKIs tested, 11 effectively inhibited substrate uptake by some transporters. Two interactions had IC50 and Ki values in the nanomolar range: the inhibition of OATP1A2- and OATP2B1-mediated estrone-3-sulfate uptake by cediranib and erlotinib, respectively. Potent inhibitory interactions were recommended for further clinical DDI studies.