The unbound fraction fu primarily affects which two pharmacokinetic aspects?

• A. Absorption rate and distribution
• B. Bioavailability and half-life
• C. Clearance and free drug exposure
• D. Metabolism rate and excretion

Answer: (C)

The unbound fraction tells you how much drug is free to act and be cleared. Only the unbound drug is available for metabolism and excretion, so changing fu directly changes how quickly a drug is eliminated—its clearance. At the same time, pharmacologic effect and toxicity depend on the free concentration, not the total one, so fu sets the amount of drug exposed in the body in its active form (the free drug exposure). In practical terms, free concentration equals fu times total concentration, and the free AUC equals fu times the total AUC.