STEREOSELECTIVE INTERACTIONS OF ORGANIC CATIONS WITH THE ORGANIC CATION TRANSPORTER IN OK CELLS

Recent studies have suggested that certain organic cations, such as pindolol and the diastereomers, quinine and quinidine, may be stereoselectively secreted by the kidney in humans. The goal of this study was to determine if the enantiomers of pindolol, verapamil, and disopyramide and the diastereomers, quinine and quinidine, interact stereoselectively with the organic cation transporter in the brush border membrane of the opossum kidney cell line. All organic cations tested inhibited the uptake of tetraethylammonium (TEA). The IC50 values (mean +/- SD) were as follows: quinine (17 +/- 2 muM), quinidine (51 +/- 13 muM, S-(-)-pindolol (23 +/- 4 muM), R-(+)-pindolol (30 +/- 4 muM), S-(-)-verapamil (0.4 +/- 0.04 muM), R-(+)-verapamil (7 +/- 2 muM), R-(-)-disopyramide (27 +/- 4 muM), and S-(+)-disopyramide (66 +/- 12 muM). Each individual organic cation pair showed significant stereoselective differences in their IC50 values, with quinine, S-(-)-pindolol, S-(-)-verapamil, and R-(-)-disopyramide being the more potent species. Both enantiomers of pindolol, quinine, and quinidine appear to exhibit simple competitive inhibition of TEA uptake based upon a derived slope similar to 1.0, using a sigmoidal inhibition model. The enantiomers of verapamil and disopyramide exhibited a slope of much less than 1.0, suggesting a more complex interaction of these organic cations with the TEA transporter. Our results suggest that organic cations stereoselectively interact with the organic cation transporter in the brush border membrane of OK cells. Stereoselective interactions with the organic cation transporter may be responsible for the stereoselective renal clearance of basic drugs known to occur in humans.