For a highly protein-bound drug, how is interindividual variability likely to manifest?

• A. Clearance shows greater variability than unbound concentrations
• B. Both equally variable
• C. No variability
• D. Unbound concentrations show greater variability than clearance

Answer: (D)

When a drug binds tightly to plasma proteins, the part that exerts effect and is cleared is the unbound fraction, not the total amount. The fraction unbound (fu) can vary between people because of differences in protein levels (like albumin or AAG), disease states, and competing drugs. Since unbound concentration equals fu times the total concentration, small changes in fu can produce relatively large changes in the unbound concentration for a given total concentration.

Clearance, on the other hand, depends on the intrinsic clearance of the unbound drug times fu (simplified CL = CLint × fu). The intrinsic clearance part tends to be fairly consistent across individuals, so even when fu varies, the overall clearance does not vary as much as the unbound concentration does. In practical terms, you’ll see greater interindividual variability in the unbound (active) drug levels than in the clearance across different people.

So, for a highly protein-bound drug, unbound concentrations show greater variability between individuals than clearance.