If a drug is a substrate for P-gp, and a P-gp inducer is co-administered, what is the expected effect on CNS exposure?

• A. Increase
• B. Decrease
• C. No change
• D. Uncertain

Answer: (B)

P-glycoprotein at the blood-brain barrier acts as an active efflux pump that limits how much of a drug can enter the brain. If the drug is a substrate for P-gp, it's being pumped back into the blood, which keeps CNS concentrations low. When a P-gp inducer is given, it increases the amount and activity of P-gp at the barrier. This enhances the efflux of the substrate from the brain back to the blood, leading to less drug accumulating in the CNS. Therefore, CNS exposure is decreased. Remember that induction takes time to upregulate transporter expression, so the effect may not be immediate.