Among highly bound drugs, variability is greater in clearance or free concentrations?

• A. Greater variability in clearance
• B. No variability in either
• C. Less variability in both
• D. Greater variability in free concentrations

Answer: (D)

For drugs that are highly protein-bound, only the unbound fraction is free to distribute, exert an effect, and be cleared. That unbound fraction is small and can vary a lot between people because of differences in albumin levels, competing drugs that displace binding, disease states, and other patient-specific factors. A small change in the fraction unbound can produce a relatively large change in the free concentration, even if the total concentration (bound plus unbound) stays similar, since most of the drug is tied up in the bound reservoir. The bound pool acts as a buffering reservoir, keeping total levels more stable while free concentrations fluctuate more with binding changes. Since clearance depends on the unbound drug, variability in the free fraction translates into variability in exposure, but the observable interindividual variability is typically greatest in free concentrations for these drugs.