Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells

In human proximal tubules, organic cations are taken up from blood into cells by human organic cation transporter 2 [hOCT2/ solute carrier (SLC) 22A2] and then eliminated into the lumen by apical H⁺/organic cation antiporters, human multidrug and toxin extrusion 1 (hMATE1/SLC47A1) and hMATE2-K (SLC47A2). To evaluate drug interactions of cationic drugs in the secretion process, epithelial cells engineered to express both hOCT2 and h MATE transporters are required to simultaneously evaluate drug interactions with renal basolateral and apical organic cation transporters. In the present study, therefore, we assessed the drug interaction between cimetidine and metformin with double-transfected Madin-Darby canine kidney cells stably expressing both hOCT2 and hMATE1 as an in vitro model of the proximal tubular epithelial cells. The basolateral-to-apical transport and intracellular accumulation of [ ¹⁴C]metformin by a double transfectant were markedly inhibited by 1 mM cimetidine at the basolateral side. On the other hand, 1 uμM cimetidine at the basolateral side moderately decreased the basolateral-to-apical transport of [¹⁴C]metformin and significantly increased the intracellular accumulation of [¹⁴C]metformin from the basolateral side, suggesting that cimetidine at a low concentration inhibits apical hMATE1, rather than basolateral hOCT2. Actually, in concentration-dependent inhibition studies by a single transporter expression system, such as human embryonic kidney 293 stably expressing hMATE1, hMATE2-K, or hOCT2, cimetidine showed higher affinity for hMATEs than for hOCT2. These results suggest that apical hMATE1 is involved in drug interactions between cimetidine and cationic compounds in the proximal tubular epithelial cells.