Involvement of Human Multidrug and Toxin Extrusion 1 in the Drug Interaction between Cimetidine and Metformin in Renal Epithelial Cells

Abstract

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 ϩ /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 hMATE 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-trans- ]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.

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

“…In some cases, the inhibition of MATE1 and MATE2K at the apical membrane likely increases drug concentrations within the renal cells, resulting in enhanced renal toxicity. Similar to vandetanib, cimetidine is a more potent inhibitor of MATE1 and MATE2K than OCT2, and cimetidine at a low concentration inhibits apical MATE1 rather than basolateral OCT2 (Tsuda et al, 2009). Likewise, in vitro inhibition potency values against cell lines indicate that PYR is a more potent inhibitor of MATE1-HEK and MATE2K-HEK cells (P , 0.0001; Table 1), which is consistent with recent reports suggesting that both serve as the loci of the PYR-metformin and PYR-Nmethylnicotinamide DDI Ito et al, 2012).…”

Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

“…To investigate chloroquine as a substrate of the OCT2-MATE1 system, we used MDCK-OCT2, MDCK-MATE1, and MDCK-OCT2-MATE1 cells grown as polarized epithelial monolayers on transwell filters. This experimental setup has been proposed as an appropriate in vitro model to evaluate the cooperative OCT2-and MATE1-mediated tubular transport of cationic compounds (20,34,40). The model allows quantification of intracellular chloroquine concentrations as well as of transcellular chloroquine transport (measured in the apical compartment) after addition of chloroquine to the basal compartment.…”

Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open‐label, drug–drug interaction study

“…Probenecid is also an OAT1/3 inhibitor. Additionally, cimetidine is the recommended OCT2 and MATE inhibitor 7, 11, 12, 13. Therefore, a drug–drug interaction study was conducted in healthy subjects to determine the effects of probenecid and cimetidine on mirogabalin pharmacokinetics (PK).…”