Most drugs are primarily bound to plasma proteins such as albumin, with only a small fraction remaining unbound. This unbound free fraction is equal to one minus the fraction that is bound. Acidic drugs reversibly bind to plasma albumin to form large, inactive complexes that are incapable of diffusing across biological barriers. Such drug-protein complexes serve as drug reservoirs. When the concentration of free drugs declines, the complexes rapidly dissociate, releasing the free drug and maintaining the free fraction. The amount of protein-bound drugs is influenced by the concentration of free drug and protein, the number of binding sites and the affinity between the drug and the binding sites. Different drugs or endogenous substances can competitively bind to plasma proteins. For example, the competitive binding of sulfonamide reduces albumin's affinity for bilirubin, causing the release of free bilirubin. This can increase the risk of bilirubin encephalopathy in newborns. Similarly, during exercise, fat metabolism releases high concentrations of free fatty acid into the plasma. These fatty acids displace the drugs bound to albumin and increase the concentration of free drugs.