salicylates and 3-carboxy-4-methyl-5-propyl-2-furanpropionic-acid

Impaired binding of anionic drugs to serum albumin in patients with uremia is thought to be due to the accumulation of endogenous substances that bind to albumin. In this study the displacement by the anionic drugs diazepam, warfarin, and salicylic acid, which are known to be representative drugs for the binding sites on the albumin molecule, of several endogenous ligands that bind to albumin in uremic serum was examined. The free fractions of the ligands bound to albumin were separated by ultrafiltration in the presence and the absence of test drugs and assayed by high-performance liquid chromatography. Diazepam displaced indoxyl sulfate (IS), hippuric acid (HA), and indole-3-acetic acid (IAA), and warfarin displaced IS, HA, ISAA, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid from serum albumin. However, salicylic acid did not displace the substance examined. The methods reported here are useful for determining the binding sites of the endogenous ligands on albumin and to clarify the drug-ligand interaction on albumin molecule in uremic serum.

Topics: Binding Sites; Furans; Hippurates; Humans; Indican; Indoleacetic Acids; Propionates; Protein Binding; Salicylates; Salicylic Acid; Serum Albumin; Uremia; Warfarin

We quantified indoxyl sulfate in uremic serum by using internal-surface reversed-phase high-performance liquid chromatography. Its concentrations were markedly increased in chronic hemodialysis patients, and were significantly but weakly correlated with the concentrations of creatinine and beta 2-microglobulin in these patients' serum, and with the duration of their hemodialysis treatment. Indoxyl sulfate could not be removed effectively by conventional hemodialysis because of its strong binding to serum albumin. Equilibrium dialysis demonstrated that indoxyl sulfate inhibited the binding of salicylate to albumin, and that 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid inhibited the binding of indoxyl sulfate to albumin. In conclusion, indoxyl sulfate was markedly accumulated in uremic serum, and inhibited drug binding.

Topics: Albumins; beta 2-Microglobulin; Chromatography, High Pressure Liquid; Furans; Humans; Indican; Propionates; Renal Dialysis; Salicylates; Uremia

3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-ethyl-2-furanpropionic acid and 3-carboxy-5-propyl-2-furanpropionic acid were detected in uremic serum using gas chromatography-mass spectrometry. Mass chromatography revealed that the serum concentrations of the furancarboxylic acids especially 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, were increased in the chronic hemodialysis patients and that the acids could not be removed by conventional hemodialysis due to their strong binding to plasma protein. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid was also quantitated in uremic serum by high-performance liquid chromatography. Serum level of the acid in uremic patients showed significant but weak correlation with serum level of urea and duration on hemodialysis. Equilibrium dialysis demonstrated that 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid and 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid inhibited the bindingof salicylate and 5,5-diphenylhydantoin to albumin. In conclusion, the furancarboxylic acids especially 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid were accumulated in uremic serum as inhibitors of drug binding.

Topics: Adult; Aged; Carrier Proteins; Chromatography, High Pressure Liquid; Female; Furans; Gas Chromatography-Mass Spectrometry; Humans; In Vitro Techniques; Male; Middle Aged; Propionates; Renal Dialysis; Salicylates; Serum Albumin; Uremia