Interaction of beta-blockers with the renal uptake transporter OCT2.
OBJECTIVE
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.


METHODS
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).


CONCLUSIONS
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.
Bachmakov
I
I
Institute of Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology and Clinical Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstrasse 17, Erlangen, Germany.
Glaeser
H
H
Endress
B
B
Mörl
F
F
König
J
J
Fromm
M F
MF
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D017298:Bisoprolol / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008687:Metformin / Q000378:metabolism*; D008790:Metoprolol / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011412:Propanolamines; C491013:SLC22A2 protein, human; D000077261:Carvedilol; D008687:Metformin; D011433:Propranolol; D008790:Metoprolol; D017298:Bisoprolol