Which combination most strongly limits a drug's ability to cross the blood-brain barrier?

Which combination most strongly limits a drug's ability to cross the blood-brain barrier?

• A. High lipophilicity
• B. Small molecular weight
• C. High polarity
• D. Absence of interactions with efflux transporters

Answer: (C)

Crossing the blood-brain barrier relies mainly on a molecule’s ability to partition into the lipid membranes of brain capillary endothelial cells and then diffuse through. Lipophilicity and small size help this diffusion, because nonpolar, low-molar-polarity molecules readily dissolve in the membrane’s lipid core and pass through. High polarity, on the other hand, keeps a molecule strongly associated with water and hydrogen-bonding networks, reducing its partitioning into the lipid phase and thus its diffusion across the barrier. So a highly polar drug faces a significant energy barrier to entry into the brain, making high polarity the strongest limiter among the given factors. The other factors would tend to facilitate, rather than hinder, passage: greater lipophilicity promotes membrane dissolution; smaller molecular weight also aids diffusion; while efflux transporter interactions can reduce brain exposure, their absence would increase crossing rather than limit it.

Crossing the blood-brain barrier relies mainly on a molecule’s ability to partition into the lipid membranes of brain capillary endothelial cells and then diffuse through. Lipophilicity and small size help this diffusion, because nonpolar, low-molar-polarity molecules readily dissolve in the membrane’s lipid core and pass through. High polarity, on the other hand, keeps a molecule strongly associated with water and hydrogen-bonding networks, reducing its partitioning into the lipid phase and thus its diffusion across the barrier. So a highly polar drug faces a significant energy barrier to entry into the brain, making high polarity the strongest limiter among the given factors.

The other factors would tend to facilitate, rather than hinder, passage: greater lipophilicity promotes membrane dissolution; smaller molecular weight also aids diffusion; while efflux transporter interactions can reduce brain exposure, their absence would increase crossing rather than limit it.