Which statements about drug protein binding are true?

• A. I, II, III, IV
• B. I, II, IV
• C. III, IV
• D. IV only

Answer: (D)

Drug protein binding determines how much of a drug is free to act, distribute, and be cleared. Binding to plasma proteins like albumin and related proteins is reversible and can become saturated as drug levels rise. Only the unbound portion of a drug is pharmacologically active and can leave the bloodstream to reach receptors, tissues, or be eliminated by the kidneys or liver. Because binding is reversible, a displaced drug can temporarily raise the free concentration and alter both effect and duration. Changes in protein levels (due to disease, age, or physiology) or interactions with other drugs can shift how much drug remains bound versus free, leading to variations in potency and clearance. With these points in mind, the true statement is the one that reflects that binding is reversible and that only the free drug is active and subject to clearance, while the other statements would conflict with these fundamental behaviors of drug-protein binding.