Datensatz

Zusammenfassung

The effect of chirality on the interaction of substrates with the organic cation transporters in the proximal tubule of rat kidney was investigated. The apparent K_i values of the enantiomers/diastereomers of ephedrine and norephedrine and the stereoisomers of deprenyl, tranylcypromine, disopyramide, verapamil, pindolol and quinine/quinidine were determined against the contraluminal organic cation transporter, the luminal H⁺/organic cation exchanger and the luminal choline⁺ transporter, using the stop-flow luminal or contraluminal capillary microperfusion method. The ephedrine/norephedrine enantiomers/diastereomers had apparent K_i values against the contraluminal organic cation transporter in the range of 0.8 to 2.4 mM, and only norpseudoephedrine showed significant enantioselectivity. The same substrates had apparent K_i values against the luminal H⁺/organic cation exchanger between 3.0 and 15.0 mM, and ephedrine, norephedrine and norpseudoephedrine showed enantioselectivity. The K_i values against the luminal choline⁺ transporter were even higher (7.2-19.1 mM) and demonstrated no enantioselectivity. The verapamil and deprenyl enantiomers showed selectivity against the luminal choline⁺ transporter, as did quinine and quinidine against the contraluminal organic cation transporter. In all other instances enantioselectivity was not observed. In no case was the difference in the K_i values of the enantiomers/isomers greater than a factor of 3. The data confirm the high degree of nonspecificity of the renal organic cation transporters. Evaluation of three-dimensional molecular models of the ephedrine enantiomers/diastereomers suggests that the spatial orientations of the amino group and, to a lesser extent, the OH group and possibly the terminal CH₃ group are of importance for different interactions with the transporters.