SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES OF THE FURAN DICARBOXYLIC-ACID, 3-CARBOXY-4-METHYL-5-PROPYL-2-FURANPROPANOIC ACID, AN INHIBITOR OFPLASMA-PROTEIN BINDING IN UREMIA

The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropan oic acid (5-propyl FPA) accumulates in the plasma of patients with chr onic renal failure and is a major contributor to the drug binding defe ct of uraemic plasma. This acid has also been implicated in several ot her aspects of the uraemic syndrome: anaemia, irregularities of thyroi d function, neurological symptoms and inhibition of active tubular sec retion. The acid is not commercially available and its synthesis, star ting with Meldrum's acid and methyl succinyl chloride, is described. T he pK(a) values were measured by titration and values of 3.2 and 3.6 r espectively were assigned to the carboxylic acid groups attached direc tly to the ring at position 3 and at position 2 (on the side-chain). T he partition coefficient (log P) between hydrochloric acid and octanol was 1.2 and the distribution coefficient (log D; octanol-phosphate bu ffer pH 7.4) was -0.59. The pK(a) values and the degree of hydrophobic character of 5-propyl FPA are consistent with those of other protein- bound acids which undergo active tubular secretion by the kidney and t his substance may serve as an endogenous marker for the effects of dru gs and disease on this process.