How does plasma protein binding influence the apparent volume of distribution and drug clearance?

• A. High plasma protein binding increases free fraction, increasing tissue distribution and Vd.
• B. High plasma protein binding lowers the free fraction, reducing tissue distribution and apparent Vd, and can influence clearance by limiting metabolism for bound drug.
• C. Plasma protein binding has no effect on Vd or clearance.
• D. Plasma protein binding always increases clearance.

Answer: (B)

Plasma protein binding controls how much drug is free to move into tissues and be cleared. Only the unbound portion can cross membranes to distribute to tissues, be metabolized, or be excreted. When a drug binds strongly to plasma proteins, the free fraction is small, so little drug leaves the plasma to distribute into tissues. This lowers the apparent volume of distribution. Clearance depends on the drug that is available for metabolism and elimination; with a small free fraction, less drug is accessible to metabolizing enzymes, so clearance can be reduced. The bound drug therefore acts as a reservoir that can slowly replenish the free pool as clearance proceeds.