Renal Excretion of Drugs and Other Xenobiotics

Besseghir, Kamel; Roch-Ramel, F

doi:10.1159/000173131

Cited by 28 publications

(21 citation statements)

References 59 publications

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“…Two SO 4 2-transporters, named NaSi-1 (Slc13a1) and Sat-1 (Slc26a1), have been well studied and are suggested to be involved in SO 4 2-reabsorption. Slc13a1 is known to be a Na + /SO 4 2-cotransporter located on the apical or brush border membrane of the epithelial cells lining the renal proximal tubule and the small and large intestine of mammals (Besseghir and Roch-Ramel, 1987;Silberg et al, 1995;Byeon et al, 1998;Markovich, 2001). Slc26a1 is known to be a multifunctional anion exchanger located on the basolateral membrane of epithelial cells that have Slc13a1 on the apical side (Bissig et al, 1994;Karniski et al, 1998;Krick et al, 2009).…”

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confidence: 99%

Molecular physiology and functional morphology of SO42– excretion by the kidney of seawater-adapted eels

Watanabe

Takei

2011

Journal of Experimental Biology

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SUMMARY Marine teleosts actively excrete SO 42-and keep the plasma concentration of this ion much lower than that of environmental seawater (SW). We used the eel as a model to study the excretory mechanism of SO 4 2-because this euryhaline species changes SO 4 2-regulation drastically after transfer from freshwater (FW) to SW. Time-course studies showed that plasma SO 4 2-concentration decreased 3days after transfer of eels from FW to SW, while urine SO 4 2-concentration increased on 1day. Detailed analyses showed that urine SO 4 2-concentration increased linearly from 6h after SW transfer; however, this did not immediately translate to increased SO 4 2-excretion because the volume of urine was decreased. We identified five SO 4 2-transporters in the eel kidney. Three of these (Slc26a1, Slc26a6b and Slc26a6c) are expressed in both SW-and FW-acclimated eels while Slc26a6a and Slc13a1 are expressed in SW-acclimated eels and FW-acclimated eels, respectively. We showed that changes in Slc26a6a and Slc13a1 gene expression occurred 1-3days after SW transfer. In SW eel kidneys, immunohistochemistry using specific antisera against each transporter protein showed that Slc26a6a and Slc26a6c are localized on the apical membrane of the P1 segment of the proximal tubule, while Slc26a6b is localized on the apical membrane and Slc26a1 on the basolateral membrane of the P2 segment. The current study revealed complex molecular mechanisms of SO 4 2-excretion in the SW eel kidney that involve segment-specific localization of multiple Slc transporters in proximal tubules and modulation of their expression in different SO 4 2-environments. This precise regulatory mechanism may endow the eel with euryhalinity.

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confidence: 99%

Molecular physiology and functional morphology of SO42– excretion by the kidney of seawater-adapted eels

Watanabe

Takei

2011

Journal of Experimental Biology

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“…Transepithelial transport of sulfate from the renal lumen to the blood compartment involves entry through the brush-border membrane (BBM) by a Na ϩ -dependent transport system, translocation across the cell and efflux across the basolateral membrane by an anion exchange system (5). Early transport studies in BBM vesicles suggested that Na ϩ -sulfate cotransport across the BBM is the rate-limiting step in the overall sulfate reabsorptive process (6,7). By expression cloning, we isolated a cDNA (NaSi-1) from rat kidney encoding a high affinity Na ϩ -dependent sulfate transporter (8).…”

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The Mouse Na+-Sulfate Cotransporter GeneNas1

Beck¹,

Markovich

2000

Journal of Biological Chemistry

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NaSi-1 is a Na ؉ -sulfate cotransporter expressed on the apical membrane of the renal proximal tubule and plays an important role in sulfate reabsorption. To understand the molecular mechanisms that mediate the regulation of NaSi-1, we have isolated and characterized the mouse NaSi-1 cDNA (mNaSi-1), gene (Nas1), and promoter region and determined Nas1 chromosomal localization. The mNaSi-1 cDNA encodes a protein of 594 amino acids with 13 putative transmembrane segments, inducing high affinity Na ؉ -dependent transport of sulfate in Xenopus oocytes. Three different mNaSi-1 transcripts derived from alternative polyadenylation and splicing were identified in kidney and intestine. The Nas1 gene is a single copy gene comprising 15 exons spread over 75 kilobase pairs that maps to mouse chromosome 6. Transcription initiation occurs from a single site, 29 base pairs downstream to a TATA box-like sequence. The promoter is AT-rich (61%), contains a number of well characterized cis-acting elements, and can drive basal transcriptional activity in opossum kidney cells but not in COS-1 or NIH3T3 cells. We demonstrated that 1,25-dihydroxyvitamin D 3 stimulated the transcriptional activity of the Nas1 promoter in transiently transfected opossum kidney cells. This study represents the first characterization of the genomic organization of a Na ؉ -sulfate cotransporter gene. It also provides the basis for a detailed analysis of Nas1 gene regulation and the tools required for assessing Nas1 role in sulfate homeostasis using targeted gene manipulation in mice.

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“…For organic anions, cellular uptake can be actively mediated by at least three different carrier systems with overlapping specif icities at the basolateral membrane-the /?-aminohippurate transporter and the related dicarboxylate and sulphate systems. Once inside the cell, the drug will enter the tubular lumen down its electrochemical gradient via an anion exchanger or a potential-driven pathway (Besseghir & Roch-Ramel 1987;Grantham & Chonko 1991;Pritchard & Miller 1993;Ullrich 1994), As a result of the sequence of these events, drugs can achieve high intracellular concentrations. In addition to a diff erence in basolateral and brush-border membrane transport, accumulation can be also caused by extensive intracellular binding or sequestration in certain cell organelles.…”

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Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

Masereeuw

Moons

Rüssel

1996

Journal of Pharmacy and Pharmacology

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The effect of protein binding on kidney function has been studied by investigating the renal accumulation and secretion of the hippurate analogue 2-methylbenzoylglycine in the isolated perfused rat kidney in the absence and presence of bovine serum albumin (BSA), Experiments were performed with either 2-5% pluronic or a combination of 2-2% pluronic and 2% BSA as oncotic agents; a wide concentration range (1-190 fig inL~1) of 2-methylbenzoylglycine was studied. Tubular secretion appeared to be a function of the amount of unbound drug in the perfusate and was best described by a model consisting of a high and low affinity Michaelis-Menten term. Parameters obtained after the analysis^of renal excretion data were maximum transport velocity for the high affinity site (TM iH ) -3 -0 db 2-8 fig min" , Michaelis-Menten constant for tubular transport for the high affinity site (KTfH ) = 0-5 ± 0-8 fig mL , maximum transport velocity for the low affinity site ^, 0 -2503:36 ¿¿g_min~ , and Michaelis-Menten constant for tubular transport for the low affinity site ( K T(l ) = 62 ±17 fig mL-1 . The compound accumulated extensively in kidney tissue, ratios up to 175 times the perfusate concentration were reached. Accumulation data were best analysed by a two-site model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity of the high affinity site (Rm,h) = 26 ± 23 f i g g~\ affinity constant for renal accumulation at the high affinity site (KaiH ) = 0*2±04 ¿¿gmL" 1, theoretical maximum capacity of the low affinity site (RM<) = 1640± 1100 jug g and affinity constant for renal accumulation at the low affinity site (K a ,l) = 60± 58 fig mL-1 .TThe very high accumulation in kidney tissue could be explained by active tubular uptake, mediated by the secretory mechanisms involved, and dependent on the amount of free drug in the perfusate. This study shows that anionic drugs, subject to active secretion, may reach high concentrations in tubular cells even at low plasma concentrations.

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Renal Excretion of Drugs and Other Xenobiotics

Cited by 28 publications

References 59 publications

Molecular physiology and functional morphology of SO42– excretion by the kidney of seawater-adapted eels

Molecular physiology and functional morphology of SO42– excretion by the kidney of seawater-adapted eels

The Mouse Na+-Sulfate Cotransporter GeneNas1

Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

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