The organic cation transporter OCT2 mediates the uptake of β ‐adrenoceptor antagonists across the apical membrane of renal LLC‐PK 1 cell monolayers

Previous studies have shown that β‐adrenoceptor antagonists may be substrates of organic cation transporters in kidney and lung. In this study we examined the transport of the β‐adrenoreceptor antagonists propranolol and metoprolol, in renal LLC‐PK 1 cell monolayers. Experiments with BCECF (2′,7′‐ bis (2carboxyethyl)‐5(6)‐carboxyfluorescein) loaded LLC‐PK 1 cell monolayers demonstrated that metoprolol and propranolol flux across the basolateral membrane was consistent with non‐ionic diffusion. Flux across the apical membrane consisted of both non‐ionic diffusion and the uptake of the cationic form of the β‐adrenoceptor antagonists. Uptake of the cationic form of metoprolol across the apical membrane was Na + ‐independent, electrogenic and sensitive to external pH. Furthermore, uptake was sensitive to inhibition by Decynium‐22 and the organic cations TEA (tetraethylammonium) and MPP + (1‐methyl 4‐phenylpyridinium). These results, allied with the apical location of the uptake mechanism suggest that β‐adrenoceptor antagonists may be substrates for the organic cation transporter, OCT2. To confirm β‐adrenoceptor antagonists as substrates for OCT2, we demonstrate, in cells transiently transfected with an epitope tagged version of hOCT2 (hOCT2‐V5):(1) Decynium‐22 sensitive [ 14 C]‐propranolol uptake, (2) cis‐inhibition of OCT2 by a range of β‐adrenoceptor antagonists and (3) metoprolol induced intracellular acidification.British Journal of Pharmacology (2000) 131 , 71–79; doi: 10.1038/sj.bjp.0703518