Which of the following factors can make a substrate more susceptible to P-gp efflux?

• A. Both more lipophilic and higher molecular weight (slower permeation)
• B. Only more lipophilic
• C. Only higher molecular weight
• D. Neither factor affects susceptibility

Answer: (C)

The key idea is that P-gp recognition and transport tend to increase with the size and bulk of the molecule. A substrate that is heavier or more sterically bulky fits the P-gp binding pocket more readily and is more likely to be bound and actively effluxed. Lipophilicity helps a compound cross membranes, but on its own it doesn’t guarantee strong interaction with P-gp; a very lipophilic but small molecule may diffuse through without being pumped, while a bulky molecule can be a substrate even if not exceptionally lipophilic. So higher molecular weight raises the chances of P-gp–mediated efflux, making it the best single factor in this context.