Renal transport mechanisms for xenobiotics: chemicals and drugs.
Using the stopped flow tubular lumen or peritubular capillary microperfusion method, the apparent Ki values of a large number of organic anions and cations against the respective transport systems were evaluated. Thereby the luminal transport system for monocarboxylates (lactate), the contraluminal and luminal transport systems for dicarboxylates (succinate), sulfate, and hydrophobic organic cations (tetraethylammonium or N1-methyl-nicotinamide), as well as contraluminal transport system for hydrophobic organic anions (para-aminohippurate, PAH) were characterized and their specificity determined. There is a partially overlapping substrate specificity between the PAH, dicarboxylate, and sulfate transport systems but also between the PAH and organic cation transport system. Xenobiotics and their metabolites are transported mainly by the organic anion (PAH) and organic cation transport systems. To test the complicated interactions possible a shot injection/urinary excretion method with simultaneous measurement of the intracellular concentration was developed. With this approach it is possible to evaluate (a) whether a substrate is net secreted or net reabsorbed, (b) whether 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 interaction. Finally, it will be discussed which ability a substrate must have to penetrate the cell membrane via a transporter, through the lipid bilayer, or both.
Ullrich
K J
KJ
Max-Planck-Institut für Biophysik, Frankfurt/Main.
Rumrich
G
G
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002412:Cations / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry; D015262:Xenobiotics / Q000493:pharmacokinetics*; D010130:p-Aminohippuric Acid / Q000378:metabolism
D002412:Cations; D008051:Lipid Bilayers; D015262:Xenobiotics; D014867:Water; D010130:p-Aminohippuric Acid