Interaction of beta-blockers with the renal uptake transporter OCT2

Aim The uptake of drugs from the blood into the renal tubular cells is a key determinant for renal secretion and may influence their systemic plasma concentrations and extrarenal effects. Metformin, used for treatment of type 2 diabetes, is taken up into renal tubular cells by the organic cation transporter 2 (OCT2). Because many patients with type 2 diabetes receiving metformin are concomitantly treated with beta-blockers, we tested whether beta-blockers can inhibit OCT2-mediated drug transport. Method Using Madin-Darby canine kidney II cells stably expressing the uptake transporter OCT2, we analysed whether the beta-blockers bisoprolol, carvedilol, metoprolol and propranolol inhibit the transport of OCT2 substrates 1-methyl-4-phenylpyridinium (MPP+) and metformin. Results Neither bisoprolol nor metoprolol significantly inhibited the uptake of MPP+, whereas a significant inhibition was observed for carvedilol und propranolol (half maximal inhibitory concentration IC50: 26.3 and 67.5 mu M) respectively. Moreover, all beta-blockers significantly inhibited OCT2-mediated metformin uptake (IC50 for bisoprolol: 2.4 mu M, IC50 for carvedilol: 2.3 mu M, IC50 for metoprolol: 50.2 mu M and IC50 for propranolol: 8.3 mu M). Conclusion These in vitro results demonstrate that alterations of uptake transporter function by beta-blockers have to be considered as potential mechanisms underlying drug-drug interactions in the kidney.