What is the effect of increasing the unbound fraction (fu) on clearance and free drug exposure?

• A. Increases both clearance and free exposure
• B. Increases clearance but decreases free exposure
• C. Increases clearance only
• D. No effect on clearance or free exposure

Answer: (A)

Unbound fraction tells us how much drug is available for clearance and for pharmacologic action. In the liver, as the fraction unbound increases, more drug is accessible to metabolic enzymes, so clearance rises. The relationship is often described by the well-stirred model, where increasing fu pushes clearance upward toward the liver’s blood-flow limit. At the same time, the portion that is unbound in plasma also increases, so the free drug concentration (and thus free exposure) goes up. Although total exposure may change as clearance changes, the unbound exposure itself increases with fu. That’s why increasing the unbound fraction raises both clearance and free exposure.