Which factor reduces central nervous system access of a drug besides the properties of the blood-brain barrier itself?

• A. High plasma protein binding.
• B. Very low molecular weight.
• C. High lipophilicity.
• D. Direct injection to bypass barriers.

Answer: (A)

The main idea is that only the unbound portion of a drug in the bloodstream can cross into the central nervous system. When a drug is highly bound to plasma proteins, most of it is tied up and unavailable to diffuse across the blood–brain barrier. This lowers the free concentration that can reach the brain, thereby reducing CNS access. In contrast, factors like very low molecular weight or high lipophilicity would enhance penetration, while directly injecting the drug can bypass barriers entirely. So high plasma protein binding specifically limits CNS exposure by reducing the unbound fraction available to cross into the brain.