Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat
The aim of this study was to understand the mechanisms that underlie the renal elimination of albumin-bound uremic toxins, particularly the highly bound furan acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), that accumulate in chronic renal failure. These toxins inhibit the binding of...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 303; no. 2; pp. 880 - 887 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.11.2002
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Subjects | |
Online Access | Get full text |
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Summary: | The aim of this study was to understand the mechanisms that underlie the renal elimination of albumin-bound uremic toxins,
particularly the highly bound furan acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), that accumulate in chronic
renal failure. These toxins inhibit the binding of acidic drugs and have various other untoward effects. The pharmacokinetics
and tissue distribution of CMPF plus three other such toxins, indoxyl sulfate, indole acetic acid, and hippuric acid, have
been examined in the anesthetized rat. The effects of p -aminohippuric (PAH) acid and tetraethylammonium on the uptake of CMPF by rat renal cortical slices in vitro were also investigated
to characterize its mechanism of uptake. Plasma and tissue concentrations of the uremic toxins were determined by high-performance
liquid chromatography. The rate of elimination of the toxins from plasma was indoxyl sulfate > hippuric acid > indole acetic
acid > CMPF. Although the renal clearance of CMPF was low, its main elimination pathway was via urinary excretion with active
tubular secretion. In renal cortical slice experiments, mutual inhibition between CMPF and PAH was observed. In addition,
α-ketoglutarate stimulated the uptake of CMPF by renal cortical slices. The base tetraethylammonium did not inhibit slice
uptake of CMPF. The pharmacokinetics of CMPF was characterized by slow plasma clearance and localization in the kidney. Furthermore,
the evidence from experiments with renal cortical slices indicates that the uptake of CMPF is mediated by an anion/dicarboxylate
exchanger, similar to that for PAH. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.303.2.880 |