To enhance CNS delivery, which modification is commonly pursued?

• A. Increase molecular weight
• B. Increase polarity
• C. Increase ionization
• D. Increase lipophilicity

Answer: (D)

Crossing the blood-brain barrier relies on the ability of the drug to diffuse through the lipid membranes that line brain capillaries. Lipid solubility is a key driver of this diffusion, so making the molecule more lipophilic helps it pass into the CNS more readily. In practice, small, nonpolar, unionized compounds penetrate brain tissue more efficiently than bulky, polar, or ionized ones. That’s why increasing lipophilicity is the common modification to enhance CNS delivery.

Keep in mind that boosting lipophilicity isn’t without trade-offs. Very lipophilic drugs can have poor water solubility, may be subject to efflux pumps, and can cause off-target effects or toxicity. Prodrug strategies are sometimes used to temporarily improve lipophilicity for BBB entry and then convert to the active form once inside the CNS.