What is the relationship between total drug concentration and free (unbound) concentration?

• A. Bound drives pharmacology; clearance of bound drug.
• B. Free concentration is equal to total concentration.
• C. Unbound has no pharmacological effect.
• D. Total = bound + unbound; only unbound drives pharmacology and is cleared.

Answer: (D)

Think of drug in the blood as existing in two forms: bound to proteins and free. The bound portion is attached to proteins like albumin and is not active—it can’t readily cross membranes or interact with targets, so it doesn’t contribute to the immediate pharmacologic effect and is not readily cleared. The unbound (free) portion is the active form that interacts with receptors to produce effect and is available for metabolic processing or renal excretion. At any moment, total concentration equals the sum of bound and unbound.

Because only the unbound drug can exert the effect and be cleared, the free concentration essentially sets how strong the pharmacologic response will be and how quickly clearance occurs. If more drug is added and binding sites are saturated, the unbound fraction can rise, increasing effect and clearance rate. Conversely, high protein binding can keep the unbound fraction small, blunting pharmacology even when total levels are high. The bound drug also serves as a reservoir, releasing free drug as the unbound pool is cleared, which can prolong the duration of action.

So the relationship is: total concentration = bound plus unbound; only the unbound portion drives pharmacology and is the form subject to clearance.