Double‐transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations

• Published in: British journal of pharmacology Vol. 163; no. 3; pp. 546 - 555
• Main Authors: König, J, Zolk, O, Singer, K, Hoffmann, C, Fromm, MF
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2011; Nature Publishing Group
• Subjects: 1-Methyl-4-phenylpyridinium - metabolism; Animals; Biological and medical sciences; Biological Transport; Cell Line; Dogs; double‐transfected cells; drug transport; Humans; Hydrogen-Ion Concentration; Hypoglycemic Agents - metabolism; MATE1; MDCK; Medical sciences; metformin; Metformin - metabolism; OCT1; OCT2; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Organic Cation Transporter 1 - genetics; Organic Cation Transporter 1 - metabolism; Organic Cation Transporter 2; organic cation transporters; Pharmacology. Drug treatments; Research Papers; Transfection; Human; Drug; Organic cation transporter; Biological transport; drug transport; organic cation transporters; In vitro; Uptake; Hypoglycemic agent; Biguanides; OCT1; OCT2; MATE1; double-transfected cells; Cations; Metformin; MDCK
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01052.x

BACKGROUND AND PURPOSE The organic cation transporters 1 (OCT1) and 2 (OCT2) mediate drug uptake into hepatocytes and renal proximal tubular cells, respectively. Multidrug and toxin extrusion protein 1 (MATE1) is a major component of subsequent export into bile and urine. However, the functional interaction of OCTs and MATE1 for uptake and transcellular transport of the oral antidiabetic drug metformin or of the cation 1‐methyl‐4‐phenylpyridinium (MPP+) has not fully been characterized. EXPERIMENTAL APPROACH Single‐transfected Madin‐Darby canine kidney (MDCK) cells as well as double‐transfected MDCK‐OCT1‐MATE1 and ‐OCT2‐MATE1 cells were used to study metformin and MPP+ uptake into and transcellular transport across cell monolayers, along with their concentration and pH dependence. KEY RESULTS Cellular accumulation of MPP+ and metformin was significantly reduced by 31% and 46% in MDCK‐MATE1 single‐transfected cells compared with MDCK control cells (10 µM; P < 0.01). Over a wide concentration range (10–2500 µM) metformin transcellular transport from the basal into the apical compartment was significantly higher in the double‐transfected cells compared with the MDCK control and MDCK‐MATE1 monolayers. This process was not saturated up to metformin concentrations of 2500 µM. In MDCK‐OCT2‐MATE1 cells basal to apical MPP+ and metformin transcellular translocation decreased with increasing pH from 6.0 to 7.5. CONCLUSIONS AND IMPLICATIONS Our data demonstrate functional interplay between OCT1/OCT2‐mediated uptake and efflux by MATE1. Moreover, MATE1 function in human kidney might be modified by changes in luminal pH values.