Changes in protein binding during disease.

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.