Which of the following is correct?

• A. Reduced binding to protein by the drug molecule will decrease the therapeutic effect of the drug
• B. Saturation of binding produces linear pharmacokinetics
• C. Bound drugs can diffuse into the tissues
• D. Only the unbound drug may be available for metabolism

Answer: (D)

Protein binding controls how much drug is free to act, be cleared, or be metabolized. A portion of the drug in the blood attaches reversibly to plasma proteins like albumin, forming a reservoir. The bound form is largely inactive pharmacologically because it cannot readily cross membranes or be metabolized. Therefore, the fraction that can be metabolized is the unbound portion. This is why only the unbound drug may be available for metabolism.

If binding were reduced, more drug would be free, which can increase therapeutic effect and also toxicity, not decrease it. Saturation of binding tends to cause nonlinear pharmacokinetics because, as dose increases, the unbound fraction rises more steeply. Bound drug generally cannot diffuse into tissues, so diffusion into tissues mainly involves the unbound portion.