Protein Binding — FRCA Primary MCQ

Correct answer: B — The unbound drug concentration at the site of action generally determines the pharmacological effect

Explanation lettering: C = shown as B · B = shown as C

C is correct. Under the conventional free-drug hypothesis, plasma protein binding is reversible and the unbound concentration reaching the target generally drives receptor interaction and pharmacological effect. Limited exceptions, such as protein-mediated hepatic uptake, do not invalidate this principle for most drugs. A is false because bound and unbound drug normally exist in dynamic equilibrium. B is false because an isolated change in binding often changes total concentration and clearance or distribution rather than causing a sustained proportional change in steady-state unbound concentration; the precise effect depends on the drug's clearance characteristics. D is false because acidic or anionic drugs bind mainly to albumin, whereas alpha-1 acid glycoprotein preferentially binds basic or cationic drugs. E is false because volume of distribution also depends substantially on tissue binding.

Reference: Schulz JA, Stresser DM, Kalvass JC. Plasma protein-mediated uptake and contradictions to the free drug hypothesis: a critical review. Drug Metabolism Reviews. 2023;55(3):205-238. https://pubmed.ncbi.nlm.nih.gov/36971325/