Which scenario would most likely increase the risk of higher unbound drug concentrations due to a drug–drug interaction?

• A. A drug with low protein binding displaces another highly bound drug
• B. A highly bound drug is displaced by another drug
• C. A drug with no protein binding binds to plasma proteins
• D. Clearance remains constant regardless of fu

Answer: (B)

The key concept is that plasma protein binding controls the unbound (free) drug concentration, which is the portion that distributes to effect and is cleared. If another drug competes for the same binding site and displaces a drug that was highly bound, the displaced drug’s unbound fraction increases. This can raise the active free drug level quickly, potentially boosting effect or toxicity.

Why the scenario where a highly bound drug is displaced by another drug is the best fit: when a drug with high affinity for the binding site is pushed off by a second drug, a noticeable amount of the previously bound drug is released into the unbound pool. Because the displaced drug was highly bound, even a small shift in binding occupancy translates into a relatively large jump in free concentration, which has clear clinical implications.

In contrast, a low protein binding drug displacing another highly bound drug would require that the displacer effectively compete for binding, but since it itself spends little time bound, the magnitude of any increase in unbound concentration of the displaced drug is typically smaller. A drug with no protein binding cannot cause displacement to affect fu in the way protein-bound drugs do, and one stating that clearance stays constant regardless of fu ignores the well-established relationship where fu influences clearance for many drugs.