A formulation of a drug highly affected by P-gp would be made to have what effect on potency?

• A. Lower potency
• B. Higher potency
• C. Same potency
• D. Variable potency

Answer: (B)

P-glycoprotein acts as an efflux pump, pushing many drugs back into the intestinal lumen or out of cells and thereby lowering how much drug actually reaches the site of action. When a formulation is highly affected by P-gp, its absorption is strongly limited by this transporter, so the drug’s exposure at the target is reduced.

But P-gp has a finite capacity. As you raise the dose or design a formulation that delivers more drug to the site, the transporter can become saturated and less able to push the drug back out. When saturation occurs, a larger fraction of the drug gets through, increasing the concentration at the site of action and producing a stronger pharmacodynamic response per unit dose. In other words, overcoming or saturating the P-gp barrier with a formulation can manifest as higher potency because more drug is effectively available where it works.

Without such strategies to counteract P-gp, potency would be reduced due to limited exposure.