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Endogenous ligand(s) decrease drug--protein binding in uremic sera: a fluorescence probe study.

G M Robertz, H J Dengler

    Klinische Wochenschrift
    |July 1, 1983
    PubMed
    Summary
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    Endogenous ligands in uremic serum impair drug binding to human serum albumin (HSA). Charcoal treatment restores binding, suggesting these ligands, not HSA structural changes, are the primary cause for reduced drug efficacy in kidney insufficiency.

    Area of Science:

    • Biochemistry
    • Pharmacology
    • Nephrology

    Background:

    • Human serum albumin (HSA) is a key transporter for many drugs in the bloodstream.
    • Uremia, a condition of severe chronic renal insufficiency, is associated with altered drug pharmacokinetics.
    • The binding of acidic drugs to HSA can be affected by endogenous substances present in uremic plasma.

    Purpose of the Study:

    • To investigate the binding characteristics of dansylglycine to human serum albumin (HSA) isolated from normal, uremic, and drug-treated sera.
    • To determine the impact of endogenous ligands and structural changes in HSA on drug binding in uremia.
    • To elucidate the mechanisms behind impaired drug binding in patients with chronic renal insufficiency.

    Main Methods:

    • Isolation and purification of human serum albumin (HSA) from normal and uremic sera, and from sera with added clofibrinic acid.

    Related Experiment Videos

  • Evaluation of dansylglycine binding to HSA using fluorescence spectroscopy.
  • Analysis of binding data using Scatchard plots and calculation of binding constants via least square approximation.
  • Charcoal treatment of HSA to assess the reversibility of binding alterations.

    • Main Results:

    • Dansylglycine binding to HSA from uremic sera was significantly reduced, primarily indicated by a lower binding affinity (n1·K1).
    • HSA from sera with added clofibrinic acid also showed decreased dansylglycine binding, mimicking the effect of endogenous ligands.
    • Charcoal treatment of uremic HSA restored dansylglycine binding to near-normal levels.
    • A minor contribution of altered HSA structure to impaired binding could not be entirely ruled out.

    Conclusions:

    • The impaired binding of acidic drugs to HSA in uremia is predominantly caused by the presence of endogenous ligands competing for binding sites.
    • These endogenous ligands interfere with the pharmacokinetics and potentially the efficacy of many acidic drugs in patients with renal insufficiency.
    • While endogenous ligands are the main factor, subtle changes in HSA structure in uremia may also play a secondary role in drug binding alterations.