P-glycoprotein
P-glycoprotein is the most famous of the body's efflux pumps — think of it as a molecular revolving door that mostly spins outward, ejecting drugs from cells. Encoded by the MDR1 (ABCB1) gene, it was first discovered making cancer cells resistant to chemotherapy by pumping the drugs back out.
It is an ATP-powered transporter studded along key barriers: the apical surface of intestinal cells (reducing oral absorption), the blood–brain barrier (limiting brain entry), the kidney tubules and bile canaliculi (boosting excretion), and the placenta (protecting the fetus). It handles a remarkably broad set of substrates, including digoxin, many chemotherapy drugs, certain immunosuppressants, opioids and HIV protease inhibitors.
P-glycoprotein is a frequent source of drug interactions. Inhibitors (such as verapamil, quinidine, ketoconazole) reduce efflux and can raise levels of substrates like digoxin, risking toxicity; inducers (such as rifampicin) increase efflux and can lower drug levels, risking failure. Genetic variation in ABCB1 contributes to person-to-person differences in drug handling.
Adding verapamil, a P-glycoprotein inhibitor, to digoxin can raise digoxin blood levels and precipitate toxicity, so the digoxin dose is usually reduced.
A classic P-glycoprotein-mediated drug interaction.
Many P-glycoprotein substrates and inhibitors overlap with the enzyme CYP3A4, so the two systems often act together to shape oral bioavailability and interactions.