RENAL TRANSPORT MECHANISMS FOR XENOBIOTICS - CHEMICALS AND DRUGS

Using the stopped flow tubular lumen or peritubular capillary microper fusion method, the apparent K(i) values of a large number of organic a nions and cations against the respective transport systems were evalua ted. Thereby the luminal transport system for monocarboxylates (lactat e), the contraluminal and luminal transport systems for dicarboxylates (succinate), sulfate, and hydrophobic organic cations (tetraethylammo nium or N1-methyl-nicotinamide), as well as contraluminal transport sy stem for hydrophobic organic anions (para-aminohippurate, PAH) were ch aracterized and their specificity determined. There is a partially ove rlapping substrate specificity between the PAH, dicarboxylate, and sul fate transport systems but also between the PAH and organic cation tra nsport system. Xenobiotics and their metabolites are transported mainl y by the organic anion (PAH) and organic cation transport systems. To test the complicated interactions possible a shot injection/urinary ex cretion method with simultaneous measurement of the intracellular conc entration was developed. With this approach it is possible to evaluate (a) whether a substrate is net secreted or net reabsorbed, (b) whethe r interference with other substrates occurs, (c) whether interference takes place at the luminal or contraluminal cell side, and (d) whether cis-inhibition or trans-stimulation is the predominant mode of intera ction. Finally, it will be discussed which ability a substrate must ha ve to penetrate the cell membrane via a transporter, through the lipid bilayer, or both.