Interaction of the stereoisomers of basic drugs with the uptake of tetraethylammonium by rat renal brush-border membrane vesicles.

Stereoselectivity in the renal clearance of drugs may be due to a stereoselective interaction with the organic cation/proton antiporter in the brush-border membrane of renal tubular epithelial cells. The interaction of the stereoisomers of chiral basic drugs with the uptake of [14C]tetraethylammonium was studied in rat renal brush-border membrane vesicles. No differences were observed in inhibition of [14C]tetraethylammonium uptake between the enantiomers of pindolol, disopyramide and bupivacaine or between (+/-)- and (+)-hydroxychloroquine and quinine/quinidine. Stereoselectivity was observed for the enantiomers of verapamil (IC50, R-verapamil 5.9 +/- 1.7 microM; S-verapamil, 3.4 +/- 1.7 microM). Stereoselectivity was also observed with the four stereoisomers of norephedrine and ephedrine in which the pairs of enantiomers differing in configuration at the carbon atom adjacent to the nitrogen atom showed stereoselectivity whereas those enantiomers having the same configuration at this carbon atom showed lack of stereoselectivity. It is concluded that when the center of chirality is adjacent to the basic functional group, the interaction with the transporter for organic cations is stereoselective. Further studies are required to elucidate the relationship between substrate stereochemistry and the organic cation transporter at both the basolateral and brush-border membranes of the renal tubular epithelial cells.