If a competing drug displaces a bound drug, what happens to fu and free exposure?

• A. fu decreases; free exposure decreases
• B. fu unchanged; free exposure unchanged
• C. fu increases; free exposure increases
• D. fu increases; free exposure decreases

Answer: (C)

Proteins in plasma bind most drugs, and only the unbound portion can act or be cleared. The fraction unbound (fu) tells us how much is free. When a competing drug displaces the bound drug from those binding sites, more of the drug is released into the unbound pool, so fu increases. With more drug in the unbound form, the free concentration rises, leading to higher free exposure. Keep in mind that this immediate rise in fu and free exposure can be followed by changes in clearance and distribution that may alter total concentrations over time, but the direct effect of displacement is an increase in fu and in free exposure.