Plasma Protein Binding

Overview

Definition: Plasma protein binding refers to how drugs attach to proteins within blood plasma.
Impact on Drug Efficacy: The degree of binding affects a drug’s ability to diffuse through cell membranes. Less bound drugs traverse more efficiently.
Common Blood Proteins: Human serum albumin, lipoprotein, glycoprotein, and globulins.

Forms in Blood: Drugs exist in two forms: bound and unbound.
Chemical Equilibrium: Reversible binding creates equilibrium between bound and unbound states.
Active Fraction: Only the unbound fraction has pharmacologic effects and can be metabolized/excreted.
- Example: Warfarin’s fraction bound is 97%; 3% is active.
Biological Half-Life: Binding can affect half-life by acting as a drug reservoir.
Binding Specificity:
- Albumin primarily binds acidic/neutral drugs.
- Alpha-1 acid glycoprotein binds basic drugs.
Medical Conditions: Can affect levels of albumin, alpha-1 acid glycoprotein, and lipoproteins.

Metabolism: Only unbound drugs undergo metabolism in the liver and tissues.
Volume of Distribution: Changes with levels of free drug due to tissue distribution.
Clearance: For rapidly metabolized drugs, clearance is hepatic blood flow dependent; for others, unbound fraction changes affect clearance.
Measurement: Plasma concentration levels measure both bound and unbound drug fractions.
Variables Affecting Unbound Fraction:
- Drug concentration, plasma protein amount/quality, and competing drugs.
- Decreased plasma protein leads to a higher unbound fraction (e.g., malnutrition, disease).

Effect of Concurrent Drug Use: Drugs can displace each other, affecting the fraction unbound.
- Example: Drug A and Drug B both protein-bound; Drug B increases Drug A’s unbound fraction.
Displacement Impact: In closed systems, displacement can significantly alter drug effect.
- Real-world systems see rapid redistribution/excretion, minimizing impact.
- Example with Warfarin and phenylbutazone demonstrates liver metabolism interference, not just displacement.

Pharmacokinetic Considerations: Understanding protein binding is crucial for drug dosing and efficacy.
Clinical Relevance: Incorrect assumptions about drug displacement can lead to dangerous clinical implications.

Toutain, P. L.; Bousquet-Melou, A. (2002). "Free Drug Fraction vs. Free Drug Concentration: A Matter of Frequent Confusion". Journal of Veterinary Pharmacology and Therapeutics.