Vol. 303, Issue 2, 880-887, November 2002

Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat

Yasuhiro Tsutsumi, Tsuneo Deguchi, Mikihisa Takano, Akira Takadate, W. Edward Lindup and Masaki Otagiri

Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (Y.T., T.D., M.O.); Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Hiroshima, Japan (M.T.); Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (A.T.); and Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, England (W.E.L.)

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, -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.