3.12
Drug Distribution: Plasma Protein Binding
Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the…
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.
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Q1: What fraction of drugs remains unbound in plasma?
Only a small fraction of drugs remains unbound in plasma, while most bind to plasma proteins like albumin. The unbound free fraction equals one minus the fraction that is bound. This free fraction is pharmacologically active and capable of producing drug effects and crossing biological barriers to reach target tissues.
Q2: How do drug-protein complexes function as drug reservoirs?
Acidic drugs reversibly bind to plasma albumin, forming large inactive complexes that cannot diffuse across biological barriers. When free drug concentration declines, these complexes rapidly dissociate to release free drug, maintaining the unbound fraction. This reservoir mechanism helps sustain drug availability and therapeutic effects throughout the body.
Q3: What factors determine the amount of protein-bound drug?
Protein-bound drug quantity depends on the concentration of free drug and protein, the number of available binding sites, and the affinity between drug and binding sites. These factors work together to establish equilibrium between bound and unbound drug states, influencing overall drug distribution and pharmacological activity.
Q4: How does competitive binding affect drug and bilirubin levels?
Different drugs and endogenous substances compete for plasma protein binding sites. When sulfonamide competitively binds to albumin, it reduces albumin's affinity for bilirubin, causing free bilirubin release. This increases bilirubin encephalopathy risk in newborns by elevating unbound bilirubin concentrations in the bloodstream.
Q5: What happens to drug-protein binding during exercise?
During exercise, fat metabolism releases high concentrations of free fatty acids into plasma. These fatty acids displace drugs bound to albumin through competitive binding, increasing the concentration of free, unbound drugs. This displacement can enhance drug bioavailability and potentially alter therapeutic effects and drug efficacy.
Q6: Why are acidic drugs unable to cross biological barriers when protein-bound?
Acidic drugs form large, inactive complexes when reversibly bound to plasma albumin. These complexes are too large and polar to diffuse across biological membranes, effectively sequestering the drug in the vascular compartment. Only the unbound free fraction can penetrate tissues and exert pharmacological effects at target sites.
Q7: How does the unbound drug fraction relate to drug efficacy?
Only the unbound free fraction of drug is pharmacologically active and capable of producing therapeutic effects. The unbound fraction is calculated as one minus the bound fraction. Changes in protein binding through competitive displacement or altered protein concentrations directly affect drug efficacy, clinical outcomes, and therapeutic success.