What is the effect of high plasma protein binding on the free fraction of a drug?

• A. Increases free fraction
• B. Decreases free fraction
• C. No effect
• D. Converts to active metabolite

Answer: (B)

High plasma protein binding reduces the free (unbound) fraction of a drug. When a larger portion of the drug is bound to proteins like albumin, less is present in the unbound form that can distribute to tissues, interact with targets, or be cleared. Only the unbound drug is pharmacologically active, so increasing binding lowers the amount available to exert effects. The bound portion serves as a reservoir, which can slow distribution and clearance, while total plasma concentration can be high even though the active free concentration is low. Binding doesn’t convert the drug into an active metabolite, and the free fraction isn’t increased by binding itself (displacement by other drugs can transiently raise the free fraction, but that’s a separate scenario).