Cellular and molecular aspects of drug transport in the kidney

Abstract

The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter (OAT), organic cation transporter (OCT), and organic anion-transporting polypeptide (oatp) gene families have been found to mediate the transport of diverse organic anions and cations. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein (MRP) gene family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs is the consequence of interaction and/or transport via these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of cloned drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions.

Identification and functional characterization of a novel human and rat riboflavin transporter, RFT1

“…There are 61 transporters (3.7% of the 1,666 known-function genes) including organic ion transporters (OAT1, OAT3, and OCTN2), Na ϩ -coupled phosphate cotransporter II (NaPi-IIa and NaPi-IIc), and aquaporin 2 (AQP2). These transporters have important physiological roles in the kidney (8,16,29,30). A recent update of this database revealed the characteristics of some unknown genes.…”

Inhibitors of HMG-CoA Reductase Reduce Receptor-mediated Endocytosis in Human Kidney Proximal Tubular Cells

“…Cellular entry of such molecules is therefore dependent on active uptake by organic anion transporters (28 -30). In vivo these are mainly present on the basolateral side of the renal epithelium (28,29). Since cultured cells are attached with their basolateral membrane to the culture dish, access of pravastatin and rosuvastatin to the cells may be relatively restricted.…”

Expressions of the multidrug resistance-related proteins in the rat olfactory epithelium: A possible role in the phase III xenobiotic metabolizing function

“…In other mammalian cells and tissues, such as the liver, kidney, trachea and tumour cells, multidrug resistance P-glycoproteins (MDRs) and multidrug resistance-related proteins (MRPs) are known to extrude xenobiotics as phase III xenobiotic metabolizing pumps, and these molecules show polarity localization in each cell [1,7,21]. MRPs were more strongly than MDRs involved in the excretion of phase II conjugated xenobiotics [10,19].…”