Drug secretion systems in renal tubular cells: functional models and molecular identity.
For the last several decades, functional characterization of renal drug handling has provided the conceptual framework of drug transport, especially drug secretion by the renal tubular cells. Functional models have been postulated for the two distinct groups of drugs with regard to their ionization characteristics at physiological pH (i.e., organic cations and organic anions). Organic cations are predicted to cross the basolateral membranes through a potential-sensitive uptake system along an inside-negative potential gradient, with secretion of organic cations into urine across apical membranes appearing to occur via a proton-organic cation antiport system. Organic anions are predicted to enter the cells against an electrical-potential gradient through basal membranes via an organic anion-dicarboxylic acid exchanger. Secretion of organic anions into urine across apical membranes is less well characterized, but the presence of an organic anion exchanger and a potential-driven transporter is hypothesized. Recent data obtained using molecular biology techniques have helped to elucidate molecular identity of each system postulated in these models. Novel drug transport proteins have also been discovered that were not part of the original organic cation/anion model, such as P-glycoprotein for hydrophobic neutral and cationic compounds. Moreover, the search for homologous genes of these transporters has led to the discovery of previously unknown transporter proteins, whose function has yet to be identified. Integral roles of these transport proteins in overall tubular handling of drugs remain to be determined.
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Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. ito@sickkids.on.ca
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000838:Anions / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D010599:Pharmacokinetics; D051381:Rats; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000838:Anions; D002352:Carrier Proteins; D002412:Cations