If tissue binding saturates at high concentrations, which outcome is most consistent with the change in unbound fraction (fu) and apparent volume of distribution (Vd)?

• A. fu decreases and Vd decreases
• B. fu remains unchanged and Vd remains unchanged
• C. fu increases and Vd decreases
• D. fu increases and Vd increases

Answer: (D)

When tissue binding is saturable, there is a finite capacity for drug to be held in tissues. At higher drug concentrations, those binding sites become filled, so additional drug cannot be sequestered in tissue and remains more free in the body fluids. Since only the unbound (free) drug can cross membranes and distribute into tissues, the fraction unbound in plasma, fu, increases as dose rises. With more drug in the unbound form, more can move into tissues, so the apparent volume of distribution grows. In short, saturable tissue binding releases more free drug at high concentrations, boosting both fu and Vd.