Plasma clearance in the rat of a furan dicarboxylic acid which accumulates in uremia.
The furan dicarboxylic acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and has been implicated in several aspects of the uremic syndrome: the defective binding of organic acids in uremic plasma, inhibition of active tubular secretion, anemia and the severity of neurological symptoms. Evidence from experiments with rat kidney slices suggests that 5-propyl FPA undergoes active tubular secretion, and so its clearance after an intravenous bolus dose (5 mg/kg; 21 mumol/kg) was investigated in anaesthetized female Wistar albino rats in vivo. The effects of intravenous bolus doses of p-aminohippuric acid (PAH) and probenecid on the clearance of this dose of 5-propyl FPA were also studied. The mean values (N = 16) for plasma half-life, plasma clearance and apparent volume of distribution of 5-propyl FPA were 3.6 hours, 2.4 ml . min(-1) . kg(-1) and 0.69 liter . kg(-1), respectively. An equimolar dose of PAH did not affect the clearance of 5-propyl FPA, but a tenfold higher molar dose of PAH (40.4 mg/kg) increased the area under the plasma-concentration time curve of 5-propyl FPA, and there was a trend towards a decrease in the clearance and a prolongation of the half-life. Probenecid at a fivefold higher dose than 5-propyl FPA had a similar effect to PAH and increased the AUC of 5-propyl FPA. PAH and probenecid decreased the plasma clearance of 5-propyl FPA, which is evidence that this uremic metabolite undergoes active tubular secretion. It follows that 5-propyl FPA could therefore inhibit the secretion of other organic acids.
Costigan
M G
MG
Department of Pharmacology and Therapeutics, University of Liverpool, England, United Kingdom.
Lindup
W E
WE
D000818:Animals; D005260:Female; D005663:Furans / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology; D011422:Propionates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012076:Renal Agents / Q000008:administration & dosage / Q000494:pharmacology; D014511:Uremia / Q000097:blood*; D010130:p-Aminohippuric Acid / Q000008:administration & dosage / Q000494:pharmacology
D005663:Furans; D011422:Propionates; D012076:Renal Agents; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; D011339:Probenecid; D010130:p-Aminohippuric Acid