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Changes in protein binding during disease
Abstract:
Disease states can alter protein binding of antimicrobials by either a reduction in the concentration of serum proteins or the accumulation of endogenous compounds, such as bilirubin and free fatty acids (FFA), that affect drug-protein interactions. In terms of protein concentration, extremely low levels of albumin (less than 2.5 m/100 ml) are required to markedly reduce binding of antimicrobials. In vitro addition of high concentrations of bilirubin and FFA to normal serum reduces binding of most antimicrobials. However, binding of some antibiotics appears to be enhanced at lower concentrations of FFA probably by an allosteric mechanism. These in vitro observations have been confirmed in sera from patients during heparin administration and patients with hyperbilirubinemia. Reduced protein binding of acidic antimicrobials in uremia appears to be associated with the accumulation of another, as yet unknown, endogenous binding inhibitor. Significant reduction in protein binding can affect the distribution of drugs and results of microbiologic assays.
Insights
Disease states significantly impact antimicrobial protein binding through altered serum protein levels or accumulated compounds like bilirubin and free fatty acids (FFA). These changes affect drug distribution and assay results.
Area of Science:
- Pharmacology
- Clinical Chemistry
- Microbiology
Background:
- Disease states can alter antimicrobial protein binding.
- This alteration is due to changes in serum protein concentration or accumulation of endogenous compounds like bilirubin and free fatty acids (FFA).
Purpose of the Study:
- To investigate how disease states affect antimicrobial protein binding.
- To understand the impact of altered protein concentrations and endogenous compounds on drug-protein interactions.
Main Methods:
- In vitro studies involving addition of bilirubin and FFA to normal serum.
- Analysis of patient sera from individuals with hyperbilirubinemia and during heparin administration.
- Investigation of antimicrobial binding in uremic patient sera.
Main Results:
- Marked reduction in antimicrobial binding occurs only at extremely low albumin levels (<2.5 m/100 ml).
- High concentrations of bilirubin and FFA reduce binding of most antimicrobials in vitro.
- Some antibiotics show enhanced binding at lower FFA concentrations, potentially via allosteric mechanisms.
- Reduced binding in uremia may involve an unknown endogenous inhibitor.
- In vitro findings are corroborated by in vivo patient data.
Conclusions:
- Disease-induced alterations in serum proteins and endogenous compounds significantly affect antimicrobial protein binding.
- These changes can influence drug distribution and the accuracy of microbiologic assays.
- Further research is needed to identify the endogenous inhibitor present in uremia.