Which alteration would most likely increase a drug's brain exposure?

Which alteration would most likely increase a drug's brain exposure?

• A. Increased molecular weight
• B. Decreased lipophilicity
• C. Inhibition of efflux transporters at BBB
• D. Increased ionization at physiological pH

Answer: (C)

The blood-brain barrier tightly controls what enters the brain, and one major factor is efflux transporters like P-glycoprotein that actively pump many drugs back into the blood. If those efflux pumps are inhibited, a drug that is normally pushed out can accumulate in the brain, increasing brain exposure. This is especially true when the drug is a substrate of these transporters, so blocking them allows higher brain concentrations and a larger brain-to-plasma exposure. In contrast, making the molecule heavier tends to hinder crossing the barrier by passive diffusion, lowering brain exposure. Reducing lipophilicity similarly impairs membrane passage, also decreasing brain penetration. Increasing ionization at physiological pH reduces permeability across the lipid membranes of the BBB, again lowering brain exposure. Thus, inhibiting efflux at the BBB is the most effective way among the options to increase brain exposure.

The blood-brain barrier tightly controls what enters the brain, and one major factor is efflux transporters like P-glycoprotein that actively pump many drugs back into the blood. If those efflux pumps are inhibited, a drug that is normally pushed out can accumulate in the brain, increasing brain exposure. This is especially true when the drug is a substrate of these transporters, so blocking them allows higher brain concentrations and a larger brain-to-plasma exposure.

In contrast, making the molecule heavier tends to hinder crossing the barrier by passive diffusion, lowering brain exposure. Reducing lipophilicity similarly impairs membrane passage, also decreasing brain penetration. Increasing ionization at physiological pH reduces permeability across the lipid membranes of the BBB, again lowering brain exposure. Thus, inhibiting efflux at the BBB is the most effective way among the options to increase brain exposure.