P-glycoprotein interactions

P-glycoprotein (MDR1) - The Body's Bouncer

• Function: ATP-dependent efflux pump encoded by the MDR1 gene. Actively transports drugs out of cells, ↓ absorption & penetration into protected sites.
• Key Locations:
  • Intestinal epithelium: ↓ drug absorption.
  • Blood-brain barrier: Limits CNS entry.
  • Renal tubules: ↑ drug elimination.
  • Tumor cells: Contributes to multi-drug resistance (MDR).

• Inhibitors (↑ Drug Levels):
  • Verapamil
  • Quinidine
  • Macrolides (e.g., erythromycin)
  • Azole antifungals (e.g., ketoconazole)
• Inducers (↓ Drug Levels):
  • Rifampin
  • St. John's Wort
  • Carbamazepine

⭐ Exam Favorite: Co-administration of digoxin with a P-gp inhibitor (e.g., verapamil, quinidine) can ↑ digoxin levels, leading to toxicity. Always monitor for bradycardia, nausea, and visual disturbances.

P-gp Interactions - The Gatekeepers

• Core Function: P-glycoprotein (P-gp), from the MDR1 gene, is a key ATP-dependent efflux transporter. It protects tissues by actively pumping a wide variety of drugs out of cells, which reduces intracellular drug concentration and overall bioavailability.

• Key Sites & Effects:

  • Intestinal epithelium → ↓ Oral drug absorption.
  • Blood-brain barrier → ↓ CNS drug penetration.
  • Renal proximal tubules → ↑ Renal drug excretion.
  • Hepatocytes → ↑ Biliary drug excretion.
  • Tumor cells → Contributes to multi-drug resistance in chemotherapy.

• P-gp Inhibitors → ↑ Substrate Levels & Toxicity:

  • Mechanism: Block the P-gp pump, increasing absorption and decreasing clearance of substrates.
  • Examples: Macrolides (Clarithromycin), Azoles (Ketoconazole), Protease Inhibitors (Ritonavir), Amiodarone, Verapamil, Diltiazem, Cyclosporine.

• P-gp Inducers → ↓ Substrate Levels & Efficacy:

  • Mechanism: Upregulate P-gp expression, decreasing absorption and increasing clearance of substrates.
  • Examples: Rifampin, St. John's Wort, Carbamazepine, Phenytoin, Phenobarbital.

⭐ Digoxin has a narrow therapeutic index and is a classic P-gp substrate. Co-administration with an inhibitor like Amiodarone or Verapamil can double its concentration, risking life-threatening cardiotoxicity. Always consider dose reduction.

📌 P-gp Inhibitors cause drug levels to Increase. P-gp Inducers cause drug levels to Decrease.

Clinical Correlations - Patient Impact

• P-gp Inhibition: ↑ absorption and ↓ clearance of substrates, leading to ↑ plasma concentration and toxicity.

  • Key Inhibitors: Verapamil, amiodarone, quinidine, macrolides (e.g., clarithromycin), azole antifungals, protease inhibitors.
  • Clinical Impact: Co-administration of verapamil with digoxin ↑ digoxin levels, risking bradycardia and AV block.

• P-gp Induction: ↓ absorption and ↑ clearance of substrates, causing ↓ plasma concentration and therapeutic failure.

  • Key Inducers: Rifampin, St. John's wort, carbamazepine, phenytoin.
  • Clinical Impact: Rifampin ↓ dabigatran levels, increasing the risk of stroke or systemic embolism.

⭐ Digoxin toxicity is a classic adverse effect precipitated by P-gp inhibitors like verapamil or amiodarone, which reduce its renal clearance.

High‑Yield Points - ⚡ Biggest Takeaways

• P-glycoprotein (P-gp) is an ATP-dependent efflux pump that transports drugs out of cells.
• It is primarily located in the gut, kidneys, and blood-brain barrier to limit drug absorption and distribution.
• P-gp inducers (e.g., Rifampin, St. John's wort) ↓ levels of substrates like Digoxin, risking therapeutic failure.
• P-gp inhibitors (e.g., Verapamil, Ketoconazole) ↑ levels of substrates, increasing toxicity risk.
• A key mechanism of multidrug resistance in cancer cells.