II. Physiology

  1. P-Glycoprotein (P-gp) is efflux transporter
    1. Categorized as a Adenosine Triphosphate-binding casette (ABC) drug uptake/efflux transporter
    2. Transports drugs out of cells and into intestinal lumen, urine or bile
    3. Prevents some agents from crossing the blood-brain barrier
  2. Substrates of P-gp have altered intestinal excretion in the presence of the inducers and inhibitors below
  3. Many Drug Interactions previously attributed to CYP3A4 are due to P-Glycoprotein effects
    1. Digoxin is not metabolized by CYP3A4 but it is affected significantly by P-Glycoprotein
    2. Digoxin Toxicity is increased with Clarithromycin, Dronedarone, Amiodarone
      1. Decrease oral Digoxin doses by 50% when these P-gp inhibitors are used concurrently
    3. Digoxin levels are decreased when used with Rifampin and Phenytoin
      1. Increase oral Digoxin doses by 30% when these P-gp inducers are used concurrently
  4. Some P-gp substrates are affected by both P-gp and CYP3A4
    1. Apixaban, Dabigatran, Rivaroxaban should be avoided with Clarithromycin and itraconzaole
      1. Strong inhibitors of both P-gp and CYP3A4
      2. Increased risk of bleeding (due to increased serum levels)
    2. Apixaban, Dabigatran, Rivaroxaban should be avoided with Rifampin, Phenytoin, St Johns Wort
      1. Inducers of both P-gp and CYP3A4
      2. Increased risk of clotting (due to decreased serum levels)
  5. References
    1. (2013) Presc Lett 20(10): 58 [PubMed]

III. Drug Interactions: P-Glycoprotein Substrates

IV. Drug Interactions: P-Glycoprotein Inhibitors (result in decreased clearance of substrates with risk of toxicity)

  1. Amiodarone
  2. Clarithromycin (strong)
  3. Conivaptan (strong)
  4. Cyclosporine
  5. Dronedarone
  6. Elacridar
  7. Erythromycin
  8. Garlic Supplement
  9. Ketoconazole (strong)
  10. Itraconazole (strong)
  11. Nelfinavir
  12. Paliperidone
  13. Quinidine
  14. Reserpine
  15. Risperidone
  16. Ritonavir (strong)
  17. Saquinavir
  18. Tacrolimus
  19. Valspodar
  20. Verapamil
  21. Voriconazole

V. Drug Interactions: P-Glycoprotein Inducers (result in increased clearance of substrates with risk of inadequate serum levels)

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