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Drug transport by Organic Anion Transporters (OATs)
No full textCommon to all so far functionally characterized Organic Anion Transporters (OATs) is their broad substrate specificity and their ability to exchange extracellular against intracellular organic anions. Many OATs occur in renal proximal tubules, the site of active drug secretion. Exceptions are murine Oat6 (nasal epithelium), human OAT7 (liver), and rat Oat8 (renal collecting ducts). In human kidneys, OAT1, OAT2, and OAT3 are localized in the basolateral membrane, and OAT4, OAT10, and URAT1 in the apical cell membrane of proximal tubule cells, respectively. In rats and mice, Oat1 and Oat3 are located basolaterally, and Oat2, Oat5, Oat9, Oat10, and Urat1 apically. Several classes of drugs interact with human OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, beta-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs. For most drugs, interaction was demonstrated in vitro by inhibition of OAT-mediated transport of model substrates; for some drugs, transport by OATs was directly proven. Based on IC50 values reported in the literature, OAT1 and OAT3 show comparable affinities for diuretics, cephalosporins, and nonsteroidal anti-inflammatory drugs whereas OAT2 has a lower affinity to most of these compounds. Drug-drug interactions at OAT1 and OAT3 may retard renal drug secretion and cause untoward effects. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, and OAT10 to nicotinate absorption. OAT4 is in addition able to release drugs, e.g. diuretics, into the tubule lumen. (C) 2012 Elsevier Inc. All rights reserved
Organic anion transporters of the SLC22 family: Biopharmaceutical, physiological, and pathological roles
No full textThe human organic anion transporters OAT1, OAT2, OAT3, OAT4 and URAT1 belong to a family of poly-specific transporters mainly located in kidneys. Selected OATs occur also in liver, placenta, and brain. OATs interact with endogenous metabolic end products such as urate and acidic neutrotransmitter metabolites, as well as with a multitude of widely used drugs, including antibiotics, antihypertensives, antivirals, anti-inflammatory drugs, diuretics and uricosurics. Thereby, OATs play an important role in renal drug elimination and have an impact on pharmacokinetics. In this review we focus on the interaction of human OATs with drugs. We report the affinities of human OATs for drug classes and compare the putative importance of individual OATs for renal drug excretion. The role of OATs as sites of drug-drug interaction and mediators cell toxicity, their gender-dependent regulation in health and diseased states, and the possible impact of single nucleotide polymorphisms are also dealt with
Transport of organic anions across the basolateral membrane of proximal tubule cells
No full textRenal proximal tubules secrete diverse organic anions (OA) including widely prescribed anionic drugs. Here, we review the molecular properties of cloned transporters involved in uptake of OA from blood into proximal tubule cells and provide extensive lists of substrates handled by these transport systems. Where tested, transporters have been immunolocalized to the basolateral cell membrane. The sulfate anion transporter I (sat-1) cloned from human, rat and mouse, transported oxalate and sulfate. Drugs found earlier to interact with sulfate transport in vivo have not yet been tested with sat-1. The Na+-dicarboxylate cotransporter 3 (NaDC-3) was cloned from human, rat, mouse and flounder, and transported three Na+ with one divalent di- or tricarboxylate, such as citric acid cycle intermediates and the heavy metal chelator 2,3-dimereaptosuccinate (succimer). The organic anion transporter I (OAT1) cloned from several species was shown to exchange extracellular OA against intracellular alpha-ketoglutarate. OAT1 translocated, e.g., anti-inflammatory drugs, antiviral drugs, beta-lactam antibiotics, loop diuretics, ochratoxin A, and p-aminohippurate. Several OA, including probenecid, inhibited OAT1. Human, rat and mouse OAT2 transported selected anti-inflammatory and antiviral drugs, methotrexate, ochratoxin A, and, with high affinities, prostaglandins E-2 and F-2alpha. OAT3 cloned from human, rat and mouse showed a substrate specificity overlapping with that of OAT1. In addition, OAT3 interacted with sulfated steroid hormones such as estrone-3-sulfate. The driving forces for OAT2 and OAT3, the relative contributions of all OA transporters to, and the impact of transporter regulation by protein kinases on renal drug excretion in vivo must be determined in future experiments
Polyspecific Organic Cation Transport: Insights into the Substrate Binding Site
Full text linkABSTRACT Positively charged endogenous and exogenous organic compounds of diverse chemical structures are transported by polyspecific organic cation transporters (OCT). In two contributions to the May 2005 issue of Molecular Pharmacology, amino acid residues within the fourth and tenth transmembrane helices of rat OCT1 are described that contribute to cation and corticosterone binding. In a three-dimensional model based on the structure of the lactose permease, these residues are located in a large grove, the binding site for biogenic amines and cationic drugs. Many widely used pharmaceuticals carry a positive or negative charge and hence are organic cations or anions. The charge renders these compounds hydrophilic, greatly facilitating their solubility in gastrointestinal fluids, plasma, and in the extra-and intracellular aqueous spaces. However, the charge largely decreases the solubility of drugs in lipids and efficiently slows uptake into or release from cells by simple diffusion across cell membranes. Rapid transport of charged drug molecules into hepatocytes for metabolism and biliary excretion, or across small bowel and proximal tubular epithelia for intestinal absorption and renal excretion, requires the presence of transporters (carriers, permeases). Given the large number of drugs and other xenobiotics, these intestinal, hepatic, and renal transporters face the formidable task of efficiently handling chemically unrelated compounds. To do so, these transporters cannot be specific for a single compound or close congeners, as in the majority of Na ϩ -coupled transporters, but must be polyspecific, showing wider recognition properties. Meanwhile, several families of polyspecific transporters for organic cations and anions exist: the ATP-driven multidrug resistance transporters [e.g., MDR, P-glycoprotein; ABCB1 (Ambudkar et al. The substrate specificity of the organic cation transporters has been studied in detail previousl
NH4+ conductance inxXenopus laevis oocytes. III. Effect of NH3
No full textExposure of Xenopus laevis oocytes to NH4Cl caused intracellular acidification, cell membrane depolarization and the generation of an inward current. To determine the contribution of uncharged NH3 and positively charged NH4+, the NH4Cl-induced inward current was measured in the presence of increasing [NH3] at constant [NH4Cl] (10 mM) or increasing [NH4Cl] at constant [NH3] (0.045 mM) with pH varying in both cases. At -70 mV, the NH4Cl-induced current was barely detectable at pH 6.5, 0.01 mM NH3, but increased successively at pH 7.5, 0.1 mM NH3 and pH 8.5, 1 mM NH3. In contrast, NH4Cl-associated currents were independent of changes of the [NH4Cl] at constant [NH3] and variable pH. Similar results with respect to acidification, depolarization and inward current in response to concentration and pH changes were obtained with trimethylamine HCl. Increasing concentrations of the weak acid propionate led to a reduction of the NH4Cl-induced current. These data suggest that NH3 entry may induce local alkalinization that, in turn, may trigger the opening of a conductance for NH4+ or trimethylamine-H+ entry
Molecular physiology of renal p-aminohippurate secretion
No full textRenal proximal tubules secrete various organic anions, including drugs and p-aminohippurate (PAH). Uptake of PAH from blood into tubule cells occurs by exchange with intracellular alpha -ketoglutarate and is mediated by the organic anion transporter 1. PAH exit into tubule lumen is species specific and may involve ATP-independent and -dependent transporters
Molecular characterization of the renal organic anion transporter 1
No full textOrganic anions of diverse chemical structures are secreted in renal proximal tubules. The first step in secretion, uptake of organic anions across the basolateral membrane of tubule cells, is mediated for the polyspecific organic anion transporter 1 (OAT1), which exchanges extracellular organic anions for intracellular alpha-ketoglutarate or glutarate. OAT1 orthologs cloned from various species show 12 putative transmembrane domains and possess several sites for potential posttranslational modification. The gene for the human OAT1 is located on chromosome 11q13.1 and is composed of 10 exons. Alternative splicing within exon 9 gives rise to four variants, two of which (OAT1-1 and OAT1-2) are functional. Following heterologous expression in Xenopus laevis oocytes, flounder renal OAT1 transported p-aminohippurate, glutarate, several diuretics, and the nephrotoxic agent ochratoxin A. Two cationic amino acid residues, lysine 394 and arginine 478, were found to be important for interaction with glutarate. Anionic neurotransmitter metabolites and the heavy-metal chelator, 2,3-dimercaptopropane sulfonate, interacted with the rabbit renal OAT1, which is expressed in kidneys and the retina
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