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 IC(50): 26.3 and 67.5 microM) respectively. Moreover, all beta-blockers significantly inhibited OCT2-mediated metformin uptake (IC(50) for bisoprolol: 2.4 microM, IC(50) for carvedilol: 2.3 microM, IC(50) for metoprolol: 50.2 microM and IC(50) for propranolol: 8.3 microM). 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.

Variability in human hepatic MRP4 expression: influence of cholestasis and genotype.

The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.