Mechanistic evaluation of modifications of distribution. Pharmacokinetic parameters of model organic anions in presence of a model renal tubular secretion inhibitor in rats.
The effects of DL-tropic acid (VIII) on the distribution pharmacokinetic parameters of the model compounds benzoylformic acid (I), p-methylbenzoylformic acid (II), p-ethylbenzoylformic acid (III), D-(-)-mandelic acid (IV), D-(-)-p-methyl-mandelic acid (V), D-(-)-p-ethylmandelic acid (VI), and D-(-)-p-isopropylmandelic acid (VII) were studied in rats. Since VIII is a competitive inhibitor of renal tubular secretion of I-VII and since all of these compounds (I-VIII) are negligibly bound to plasma proteins and are neither metabolized nor reabsorbed from the renal tubules, they were considered as model compounds. Therefore, changes observed in the values of the distribution pharmacokinetic parameters of I-VII were attributed to the influence of VIII on the transmembrane transport of the compounds between body compartments in rats. The decrease in the apparent volumes of the central compartments for I, IV, and VII, the increase in the apparent volumes of the peripheral compartments for IV-VII, the absence of change in the volumes of the central or peripheral compartments for the other compounds, and the increase in the ratios of the rate constants of the transfer of compounds from one compartment into another for I and IV-VII were explained in terms of the "aqueous pore" mechanism for the transmembrane transport of the anions of the compounds as well as the heteroporosity of the tissue membranes.
D000818:Animals; D000838:Anions / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D003864:Depression, Chemical; D004347:Drug Interactions; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats
D000838:Anions; D001798:Blood Proteins