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 Ͼ hippuric acid Ͼ indole acetic acid Ͼ 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, ␣-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.
We have confirmed the existence of a site II-to-site I displacement, which is very striking and pharmacologically important, because the concentration of unbound drug being displaced is much lower than expected for a competitive mechanism.
The purpose of the present study was to examine the pharmacokinetic properties of indoxyl sulphate, a harmful uraemic toxin that accumulates during chronic renal failure. The pharmacokinetics and tissue distribution of indoxyl sulphate were examined in normal and 5/6 nephrectomized (CRF) rats. The uptake process of indoxyl sulphate by rat renal cortical slices in vitro was also investigated. Endogenous indoxyl sulphate was found to be mainly distributed in the kidney. The rate of elimination of indoxyl sulphate from plasma was lower in CRF rats compared with sham-operated rats. The majority of intact indoxyl sulphate was excreted in the urine. In renal cortical slice experiments, uptake of indoxyl sulphate was a saturable process with a K(m) of 43.0 microm. Furthermore, sulphate conjugates, such as oestrone sulphate and dehydroepiandrosterone sulphate, inhibited the uptake of indoxyl sulphate to a greater extent than PAH. Thus, indoxyl sulphate is primarily eliminated from the plasma via the kidney by active tubular secretion, and renal uptake of indoxyl sulphate appears to be mediated by an organic anion transport system with a high affinity for oestrone sulphate and dehydroepiandrosterone sulphate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.