If fu varies between patients, which pharmacokinetic parameter is most directly affected?

• A. Absorption rate
• B. Clearance and unbound exposure
• C. Volume of distribution only
• D. Bioavailability only

Answer: (B)

The unbound fraction in plasma (fu) controls how much drug is available for elimination, so changes in fu across patients directly affect how quickly the drug is cleared. Since only the unbound drug is subject to metabolism and renal excretion, increasing fu increases the amount cleared per unit time, leading to higher clearance and lower overall exposure (AUC) for the total drug. At the same time, the amount of drug that is unbound in plasma is fu times the total concentration, so unbound exposure tracks fu directly. Absorption and bioavailability are governed by processes in the GI tract and first-pass effects, not by fu, and while fu can influence distribution to some extent, the clearest and most direct effect of fu variation is on clearance and unbound exposure.