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P-glycoprotein acts as an active efflux transporter on the apical surface of intestinal epithelial cells. It pumps many drugs back into the gut lumen as they attempt to cross into the bloodstream, which directly reduces how much drug is absorbed from the gut and thus shapes the amount that reaches systemic circulation and distributes to the rest of the body. Because absorption from the oral route occurs primarily in the intestine, P-gp’s activity there has the most immediate and direct impact on how much drug enters circulation and how it subsequently distributes.

Liver, lungs, and kidneys also express P-gp and influence disposition, excretion, and local distribution, but they don’t govern the initial absorption process as the intestinal barrier does.