Water-soluble or highly ionized drugs typically show what level of BBB penetration?

• A. Low penetration
• B. High penetration
• C. Variable depending on active transport
• D. Always cross

Answer: (A)

Crossing into the brain mainly depends on a drug’s ability to diffuse through the lipid membranes of the blood-brain barrier. The barrier is tight and lipid-rich, so small, nonpolar, lipophilic molecules cross readily by passive diffusion. Water-soluble or highly ionized drugs are polar or charged, which greatly hinderns their passage through the lipid bilayer. As a result, these drugs typically have limited diffusion into the central nervous system, i.e., low penetration. There are occasional exceptions when a drug is a substrate for a specific transporter, but those are specialized cases and don’t change the general rule.