How does unbound fraction fu influence volume of distribution?

• A. Higher fu generally decreases Vd.
• B. Higher fu generally increases Vd.
• C. Fu has no effect on Vd.
• D. Fu only affects clearance, not Vd.

Answer: (B)

The key idea is that the volume of distribution reflects how widely a drug spreads from the plasma into tissues. Only the unbound portion of a drug in the blood—the fraction not bound to plasma proteins—can cross membranes and equilibrate with tissues. When the unbound fraction (fu) is larger, more drug is free to leave the plasma and distribute into tissues, increasing the amount of drug in the body relative to the plasma concentration. Since Vd is defined as the total amount of drug in the body divided by the plasma concentration, more extensive distribution into tissues lowers plasma concentration for a given dose and raises the calculated Vd. Conversely, if most of the drug is bound to plasma proteins (low fu), little is free to distribute, so the drug remains largely in the vascular compartment and Vd tends to be smaller. While tissue binding and other factors can modulate this, fu is a primary driver of the extent of distribution, so higher fu generally increases Vd.