MDC Pharmacokinetics (PK) I Practice Exam

The key idea is that only the unbound drug is free to move, be metabolized, and be cleared. Protein binding acts like a reservoir, so the fraction that remains unbound (fu) is what actually drives pharmacokinetic processes.

Because only the unbound portion can cross membranes and reach sites of metabolism or excretion, fu directly influences both clearance and distribution. For clearance, especially for drugs cleared by the liver with low extraction, the clearance is largely proportional to fu times the intrinsic clearance of the drug (CL = fu × CLint in that case). For distribution, a higher fu means more drug is free to leave plasma and distribute into tissues, which increases the apparent volume of distribution. Conversely, a low fu (high binding) keeps more drug in plasma and lowers the apparent distribution into tissues.

In short, fu determines how much drug is available to be distributed, metabolized, and excreted, and thus it shapes both clearance and volume of distribution.