At high drug concentrations in a highly protein-bound drug, what happens to fu and clearance?

• A. fu decreases; clearance decreases
• B. fu increases; clearance increases
• C. fu unchanged; clearance unchanged
• D. fu decreases; clearance increases

Answer: (B)

When a drug binds to proteins like albumin, that binding can be saturable. As you increase the drug concentration, the binding sites start to fill up, and more of the drug remains unbound. This raises the unbound fraction (fu). Only the unbound drug is available for metabolism and excretion, so the amount cleared drops or rises in proportion to fu, depending on the liver’s intrinsic capacity for metabolism. With saturable binding and a non-saturated intrinsic clearance, increasing fu boosts the overall hepatic clearance, described by the well-stirred model where CL rises as fu increases (up to a limit set by hepatic blood flow). So at high concentrations for a highly protein-bound drug, fu increases and clearance increases.