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 microM). quinidine (51 +/- 13 microM), S-(-)-pindolol (23 +/- 4 microM), R-(+)-pindolol (30 +/- 4 microM), S-(-)-verapamil (0.4 +/- 0.04 microM), R-(+)-verapamil (7 +/- 2 microM), R-(-)-disopyramide (27 +/- 4 microM), and S-(+)-disopyramide (66 +/- 12 microM). 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Ott
R J
RJ
School of Pharmacy and Medicine, University of California, San Francisco 94143.
Giacomini
K M
KM
D000818:Animals; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000378:metabolism*; D002412:Cations / Q000378:metabolism*; D002460:Cell Line; D004206:Disopyramide / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D009893:Opossums; D010869:Pindolol / Q000493:pharmacokinetics; D011803:Quinine / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D014700:Verapamil / Q000493:pharmacokinetics
D002352:Carrier Proteins; D002412:Cations; D013757:Tetraethylammonium Compounds; D011803:Quinine; D010869:Pindolol; D014700:Verapamil; D004206:Disopyramide