Aromatic amino acid metabolites as potential protein binding inhibitors in human uremic plasma

Rohertz-Vaupel

1992

Eur J Clin Pharmacol

The binding capacity of human serum albumin (HSA) for small acidic molecules is known to be reduced in chronic renal failure (CRF). The contribution of competitive inhibition by accumulated endogenous ligands and of structural changes in HSA has now been evaluated. In a fluorimetric in vitro assay using HSA and two dansylated amino acids the inhibitory properties of various endogenous ligands were determined in concentration-effect studies. The effect of carbamylation of HSA on binding was also examined. The mode of inhibition, including binding parameters n and Ka, was determined. Finally, HSA binding in sera from controls and dialysis patients was compared in a modified assay. Thirty three substances were tested and were placed in 3 groups: strong inhibitors (IC50 < 3*10(-5) mol.l-1, e.g. indolyl acids, furanoic acids), medium inhibitors (IC50 > 3*10(-5), eg. vanillic acid), and no inhibition (e.g. urea, creatinine, guanidino compounds). Complete (> 80%) carbamylation of HSA reduced binding by 67% in a non-competitive mode. There was a significant reduction in the binding capacity of HSA from the dialysis patients (approximately 24%), irrespective of medication. It is concluded that the uraemic binding defect of HSA is caused by competitive inhibition by the many physiological ligands accumulated in CRF and structural modifications of HSA. The assay presented proved useful for the rapid analysis of possible HSA binding inhibitors and for testing large groups of patients, e.g. comparison of dialysis treatments, and pharmacological binding studies.

Section: Discussionsupporting

confidence: 64%

Albumin binding in uraemia: quantitative assessment of inhibition by endogenous ligands and carbamylation of albumin

Rohertz-Vaupel

1992

Eur J Clin Pharmacol

“…We think that 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid is one of the major drug-binding inhibi tors present in uremic serum, but a single substance is not responsible for drug-binding inhibition observed in uremia [29]. It is important to investigate the endogenous ligand solutes which are displacers of drugs and endoge nous substances to understand a variety of biochemical and metabolic abnormalities observed in uremic patients despite adequate hemodialytic therapy.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of an Endogenous Drug-Binding Inhibitor Present in Uremic Serum

Mabuchi

Nakahashi²

1986

Nephron

Isolation of an endogenous ligand solute from uremic serum was performed by high-performance liquid chromatography. This ligand solute inhibited the binding of diphenylhydantoin and tryptophan to plasma protein, and was considered to be one of the endogenous drug-binding inhibitors present in uremic serum. The gas chromatographic-mass spectrometric analysis revealed that this inhibitor is 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, which is known to be a constituent of urine.

“…Indoxyl sulfate is considered to be a uremic toxin, since it inhibits the drug binding of albumin [1][2][3], the erythroid colony formation [4], lymphocyte blast formation [4], and thyroxine hepatocyte transport [5] and since it stimulates the progression of glomerular sclerosis [6,7], The serum concentration of indoxyl sulfate was markedly increased in uremic patients [3,6,8,9], Indoxyl sulfate is synthesized in the liver from indole which is produced in the intestine from tryptophan by tryptophanase of such K A R C i F R ® 1996 S. Karger AG. Basel I X /-\I \V J t 0028-2766/96/074!-0072$ 10.00/0 E-Mail kargcr@kargcr.ch F ax+ 41 61 306 12 34 http:// www.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Indoxyl-β-<i>D</i>-Glucuronide in Uremic Serum: Suppression of Its Production by Oral Sorbent and Efficient Removal by Hemodialysis

Niwa

Miyazaki²,

Tsukushi³

et al. 1996

Nephron

We identified and quantified indoxyl-β-D-glucuronide in uremic serum and urine to determine the metabolism of indoles including indoxyl sulfate in uremic patients. Serum levels of indoxyl-β-D-glucuronide were markedly increased in undialyzed uremic patients, in patients on hemodialysis, and in patients on continuous ambulatory peritoneal dialysis. Urinary excretion of indoxyl-β-D-glucuronide was also increased in undialyzed uremic patients. Urinary indoxyl-β-D-glucuronide was significantly correlated with serum indoxyl sulfate, indicating that a high serum level of indoxyl sulfate leads to the enhanced synthesis of indoxyl-β-D-glucuronide. Oral sorbent (AST-120) administration markedly decreased the serum and urine levels of indoxyl-β-D-glucuronide as well as indoxyl sulfate in the undialyzed uremic patients. Serum indoxyl-β-D-glucuronide could be efficiently removed by hemodialysis despite its high protein-binding ratio of about 50%. In conclusion, the serum level of indoxyl-β-D-glucuronide increases in uremic patients due to renal insufficiency and its increased production. The production of indoxyl-β-D-glucuronide can be suppressed by oral sorbent treatment, and serum indoxyl-β-D-glucuronide can be efficiently removed by hemodialysis.