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)

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

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