Which of the following is a case where plasma concentration does NOT correlate with pharmacologic response?

• A. High salt form increases plasma concentration
• B. Linear pharmacokinetics
• C. Fixed dosing without tolerance
• D. Active metabolites

Answer: (D)

When a drug’s effect is mainly produced by an active metabolite, the pharmacologic response can decouple from the parent drug’s plasma level. The body creates a metabolite that has its own activity, and the overall effect depends on the metabolite’s concentration and activity, not just the parent drug. A classic example is codeine, which is converted to morphine in the body; analgesia comes largely from morphine, and individuals differ in how effectively they convert codeine. So two people with similar codeine concentrations can have different analgesic responses because their morphine levels differ.

In contrast, linear pharmacokinetics, fixed dosing, and salt forms mostly preserve a predictable relationship between dose, plasma concentration, and effect, so the plasma level tends to reflect the pharmacologic response. Therefore, active metabolites are the scenario where plasma concentration of the parent drug may not correlate with the observed effect.