P-Glycoprotein Interactions

• Increasing recognition as an important factor in influencing drug pharmacokinetics and efficacy

• Can significantly affect disposition of medications:

  • ? absorption, ? elimination, ? entry to CNS, testes

• P-gp inducers:

  • phenobarbital, phenytoin, rifampin, St.John’s wort

• P-gp inhibitors:

  • erythromycin, clarithromycin, diltiazem, felodipine, intraconazole, ketoconazole, nicardipine, grapefruit

Previous slide

Next slide

Back to first slide

View graphic version

• Now being increasingly recognized as having a role in pharmacokinetics of many medications, including protease inhibitors
  • oral absorption: oral bioavailability may be limited by the presence of CYP3A4 in the GI tract and liver (first-pass effect), as well as P-gp, which may transport absorbed drug back into the intestinal lumen
  • CNS exposure: in addition to other factors such as lipophilicity, plasma protein binding, molecular weight, and concentration, P-gp may play a significant role in limiting penetration of protease inhibitors into the brain

• Agents which inhibit P-gp may affect dispostion of P-gp substrates (e.g., ritonavir inhibits P-gp; may partially account for its profound effect on saquinavir metabolism)

References:

Metheny CJ, Lamb MW, Brouwer KLR, Pollack GM. Pharmacokinetic and Pharmacodynamic Implications of P-glycoprotein Modulation. Pharmacotherapy 2001; 21(7):778-796.