Affinity of Drugs to the Different Renal Transporters for Organic Anions and Organic Cations

2005 ◽  
pp. 159-179 ◽  
Author(s):  
Karl Julius Ullrich
Keyword(s):  
Organic Anions ◽  
Organic Cations ◽  
Renal Transporters

The Molecular Basis for Hepatobiliary Transport of Organic Cations and Organic Anions

2002 ◽  
pp. 89-157 ◽  
Author(s):  
Dirk K. F. Meijer ◽  
Johan W. Smit ◽  
Guido J. E. J. Hooiveld ◽  
Jessica E. van Montfoort ◽  
Peter L. M. Jansen ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Organic Anions ◽  
Organic Cations ◽  
Hepatobiliary Transport

Interactions of organic anions with the organic cation transporter in renal BBMV

1988 ◽  
Vol 254 (1) ◽  
pp. F56-F61 ◽  
Author(s):  
P. H. Hsyu ◽  
L. G. Gisclon ◽  
A. C. Hui ◽  
K. M. Giacomini
Keyword(s):  
Proximal Tubule ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Organic Anions ◽  
Renal Proximal Tubule ◽  
Ph Gradient ◽  
Transport Systems ◽  
Organic Cations ◽  
Initial Uptake

It is generally assumed that the organic cation transport system in the renal proximal tubule is specific for organic cations and the transport of organic cations is not affected by organic anions. However, there are also data in the literature demonstrating that probenecid, a classical inhibitor of organic anion transport systems, inhibits the transport of an organic cation, cimetidine, in the renal proximal tubule. In this study we investigated the effects of probenecid and furosemide on the transport of N'-methylnicotinamide (NMN) the classical substrate of the organic cation transporter, in brush-border membrane vesicles prepared from rabbit renal cortex. In the presence of a pH gradient, both probenecid (10 mM) and furosemide reduced the initial uptake of NMN. Probenecid reduced the initial uptake of NMN to 12.1% of the control values (1.19 +/- 0.26 pmol/mg) and furosemide reduced the initial uptake of NMN to 39.2%. Probenecid (10 mM) also decreased the initial transport of NMN in the absence of a pH gradient. Inhibition of the transport of NMN by probenecid was concentration dependent, with the concentration of probenecid resulting in 50% inhibition of the transport of NMN equal to 2.31 +/- 1.18 mM in the presence of a pH gradient. Probenecid appeared to be a competitive inhibitor of NMN transport. The apparent Km (mean +/- SE) of NMN transport (2.01 +/- 0.78 mM) was increased to 18.7 +/- 10 mM (P less than 0.05) by probenecid (10 mM), whereas the Vmax was not changed (125 +/- 19.2 pmol.s-1.mg-1 vs. 186 +/- 94 pmol.s-1.mg-1, P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Formation: a Concerted Action of Membrane Transporters in Hepatocytes and Cholangiocytes

Physiology ◽  
2000 ◽  
Vol 15 (1) ◽  
pp. 6-11 ◽  
Author(s):  
Akos Zsembery ◽  
Theresia Thalhammer ◽  
Jürg Graf
Keyword(s):  
Bile Acids ◽  
Membrane Transport ◽  
Functional Characterization ◽  
Organic Anions ◽  
Membrane Transporters ◽  
Organic Cations ◽  
Transport Mechanisms ◽  
Concerted Action ◽  
Bile Formation ◽  
Transport Molecules

A large number of membrane transport mechanisms in hepatocytes and cholangiocytes serves for the secretion of bile acids, various other organic anions, organic cations, lipids, and electrolytes. After their functional characterization, some of these mechanisms' individual transport molecules are now identified, allowing better understanding of inherited and acquired disorders of bile formation.

scholarly journals SLC22 family of organic cation and anion transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Bruno Hagenbuch
Keyword(s):  
Organic Cation ◽  
Drug Disposition ◽  
Organic Anions ◽  
Membrane Topology ◽  
Organic Cations ◽  
Extracellular Loop ◽  
Anion Transporters ◽  
The Family

The SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2.

Molecular aspects of hepatobiliary transport

1997 ◽  
Vol 272 (6) ◽  
pp. G1285-G1303 ◽  
Author(s):  
M. Muller ◽  
P. L. Jansen
Keyword(s):  
Multidrug Resistance ◽  
Bile Acid ◽  
Bile Acids ◽  
Bile Flow ◽  
Hepatic Uptake ◽  
Organic Anions ◽  
Transport Proteins ◽  
Organic Cations ◽  
Multidrug Resistance Protein ◽  
Resistance Protein

Generation of bile flow is a regulated, ATP-dependent process and depends on the coordinated action of a number of transporter proteins in the sinusoidal and canalicular domains of the hepatocyte. Dysfunction of any of these proteins leads to retention of substrates, with conjugated hyperbilirubinemia or cholestasis as a result. In recent years many of the transport proteins involved in bile formation have been identified, cloned, and functionally characterized. The hepatocyte sinusoidal membrane contains transport proteins for the hepatic uptake of organic anions and cations and for the uptake of bile acids. The multispecific organic anion transporting polypeptide (OATP) mediates the hepatic uptake of organic anions and a variety of organic amphiphilic compounds, including organic cations. The organic cation transporter OCT1 more specifically transports small organic cations. NTCP is the Na(+)-bile acid cotransporting protein that mediates the hepatic uptake of bile acids. The canalicular transport proteins are able to transport endogenous and exogenous metabolites into the bile against steep concentration gradients. Most of these transporters are members of the large ATP-binding cassette (ABC) superfamily, and their transport function directly depends on the hydrolysis of Mg2+/ATP. At least five ABC transporter proteins have been characterized so far: 1) the human multidrug resistance protein MDR1 mediates the excretion of hydrophobic, mostly cationic, metabolites; 2) MDR3 is involved in phosphatidylcholine secretion; 3) the canalicular bile acid transporter cBAT mediates secretion of monovalent bile salts and provides the molecular basis of bile acid-dependent bile flow; 4) SPGP, product of the P-glycoprotein sister gene, is exclusively expressed in the liver but its function is currently unknown; and 5) the human multidrug resistance protein MRP2 mediates the excretion of multivalent anionic conjugates.

Comparative insights into the mechanisms of renal organic anion and cation secretion

1991 ◽  
Vol 261 (6) ◽  
pp. R1329-R1340 ◽  
Author(s):  
J. B. Pritchard ◽  
D. S. Miller
Keyword(s):  
Organic Cation ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Cation Transport ◽  
Organic Anions ◽  
Proton Exchange ◽  
Metabolic Energy ◽  
Organic Cations ◽  
Free Concentration ◽  
Indirect Coupling

Comparative models have played a major role in defining the mechanisms that enable vertebrate proximal tubules to transport organic anions and cations from the peritubular interstitium to the urine. The unique advantages of these models and their contributions to our understanding of organic anion and cation transport mechanisms are summarized here. Recent studies of the organic anion transport system suggest that transport is coupled to metabolic energy via indirect coupling to the sodium gradient. Organic anions enter the cell across the basolateral membrane in exchange for alpha-ketoglutarate (alpha-KG), and the alpha-KG is returned to the interior via Na-alpha-KG cotransport. Indirect coupling to Na has been demonstrated in both isolated membranes and intact renal epithelial cells of species ranging from marine crustaceans to mammals. This mechanism was shown to drive not only cellular accumulation but also secretory transepithelial fluxes of organic anions. Luminal exit of secreted organic anions appears to be carrier mediated but is, at present, poorly understood, with mediated potential-driven efflux and anion exchange-driven efflux implicated in some species. As for organic anions, the renal clearance of some organic cations approaches the renal plasma flow. Although there is considerable variation in the handling of specific substrates between species, the basic properties of organic cation transport include carrier-mediated potential-driven uptake at the basolateral membrane, intracellular sequestration that reduces the free concentration of the cation, and luminal exit by organic cation-proton exchange. Reabsorptive transport is also observed for some organic cations, but its mechanisms and driving forces are not well understood.

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