A drug is a substrate for P-glycoprotein. What is the expected effect on central nervous system exposure when a P-gp inhibitor is co-administered?

• A. Increases CNS exposure
• B. Decreases CNS exposure
• C. No change in CNS exposure
• D. CNS exposure becomes unpredictable

Answer: (A)

P-glycoprotein at the blood-brain barrier acts as an efflux pump that actively removes substrates from the brain, limiting CNS exposure. When you co-administer a P-gp inhibitor, the efflux is reduced, allowing more of the substrate drug to cross into the CNS and accumulate there. So CNS exposure increases. The result can vary in magnitude based on drug affinity and inhibitor potency, but the direction is toward higher brain concentrations.