Renal organic acid transport: uptake by rat kidney slices of a furan dicarboxylic acid which inhibits plasma protein binding of acidic ligands in uremia.
The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA), accumulates in uremic plasma and inhibits the binding of various drugs and marker ligands that are organic acids. 5-Propyl FPA is excreted unchanged in human urine and active tubular secretion is likely to be involved because of its high affinity for albumin. The uptake of 5-propyl FPA by rat kidney slices has been measured and compared with that of p-aminohippurate (PAH). The mean (+/- S.D.) slice/medium ratio for uptake of 5-propyl FPA (76 microM) was 22.7 +/- 2.6 (n = 11) and for PAH (75 microM) was 15.9 +/- 3.2 (n = 9) after incubation for 90 min at 25 degrees C. 5-Propyl FPA (149-829 microM) inhibited the uptake of PAH (77 microM) in a concentration-dependent manner, and likewise, PAH (150-830 microM) inhibited the uptake of 5-propyl FPA (77 microM). The mean apparent Km and Vmax values for the uptake of 5-propyl FPA were 194 +/- 125 microM and 55 +/- 28 nmol/g kidney/min, respectively, and 487 +/- 179 and 99 +/- 46 nmol/g kidney/min, respectively, for PAH. The kinetics of inhibition of uptake of PAH by 5-propyl FPA were mainly competitive. 5-Propyl FPA is thus likely to undergo active tubular secretion in a similar way to PAH, and this furan dicarboxylic acid, therefore, has the potential to inhibit the renal excretion of various drugs, drug conjugates and other endogenous organic acids.
Henderson
S J
SJ
Department of Pharmacology and Therapeutics, University of Liverpool, England.
Lindup
W E
WE
D000818:Animals; D001693:Biological Transport, Active; D001798:Blood Proteins / Q000378:metabolism; D046508:Culture Techniques; D005260:Female; D005663:Furans / Q000032:analysis / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D011422:Propionates / Q000032:analysis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014511:Uremia / Q000378:metabolism*; D010130:p-Aminohippuric Acid / Q000032:analysis / Q000493:pharmacokinetics
D001798:Blood Proteins; D005663:Furans; D011422:Propionates; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; D010130:p-Aminohippuric Acid