Importance of OCT2 and MATE1 for the Cimetidine–Metformin Interaction: Insights from Investigations of Polarized Transport in Single- And Double-Transfected MDCK Cells with a Focus on Perpetrator Disposition

Abstract

Cimetidine decreases the renal clearance of metformin by inhibition of renal tubular cation transport, and the underlying molecular mechanisms are still not fully understood. We investigated polarized metformin transport without and with the addition of cimetidine as well as polarized cimetidine transport in double-transfected MDCK-OCT2-MATE1 cells that mimic organic cation transport processes in proximal renal tubule cells and in MDCK vector control and single-transfected MDCK-OCT2 and MDCK-MATE1 cells. At all tested concentrations (1, 10, 100 μM), the intracellular accumulation of cimetidine after administration to the basal compartment was considerably higher in MDCK-OCT2 cells compared to that in all other cells ( p < 0.001). Whereas cimetidine transcellular, basal-to-apical transport was only slightly higher in MDCK-OCT2 cells, the presence of MATE1 in the apical membrane caused a pronounced translocation of cimetidine in both single- and double-transfected cells ( p < 0.001). Transcellular, basal-to-apical metformin net transport was reduced by 89.1, 74.5, and 91.0% in MDCK-OCT2-MATE1 cells after the addition of cimetidine (100 μM) to the basal, the apical, or both compartments ( p < 0.001). In MDCK-MATE1 and MDCK-OCT2-MATE1 cells, transcellular net transport of metformin was inhibited by cimetidine with IC50 values of 8.0 and 6.6 μM, respectively. Our data confirm the relevance of MATE1 and suggest the relevance of OCT2 for the cimetidine-metformin interaction, primarily because OCT2 mediates uptake of the perpetrator cimetidine into renal proximal tubular cells and thereby to the site of the metformin exporter MATE1. This work supports the notion that a thorough understanding of transporter-mediated drug-drug interactions may require investigations on the impact of transporters on cellular uptake and transcellular transport of victim as well as perpetrator drugs.