Enhanced corneal absorption of erythromycin by modulating P-glycoprotein and MRP mediated efflux with corticosteroids

Pharm Res. 2009 May;26(5):1270-82. doi: 10.1007/s11095-008-9741-x. Epub 2008 Oct 29.


Purpose: The objectives were (i) to test in vivo functional activity of MRP2 on rabbit corneal epithelium and (ii) to evaluate modulation of P-gp and MRP2 mediated efflux of erythromycin when co-administered with corticosteroids.

Methods: Cultured rabbit primary corneal epithelial cells (rPCECs) was employed as an in vitro model for rabbit cornea. Cellular accumulation and bi-directional transport studies were conducted across Madin-Darby Canine Kidney (MDCK) cells overexpressing MDR1 and MRP2 proteins to delineate transporter specific interaction of steroids. Ocular pharmacokinetic studies were conducted in rabbits following a single-dose infusion of erythromycin in the presence of specific inhibitors and steroids.

Results: Bi-directional transport of erythromycin across MDCK-MDR1 and MDCK-MRP2 cells showed significant difference between BL-AP and AP-BL permeability, suggesting that erythromycin is a substrate for P-gp and MRP2. Cellular accumulation of erythromycin in rPCEC was inhibited by steroids in a dose dependent manner. MK571, a specific MRP inhibitor, modulated the aqueous humor concentration of erythromycin in vivo. Even, steroids inhibited P-gp and MRP2 mediated efflux with maximum increase in k(a), AUC(0-infinity), C(max) and C(last) values of erythromycin, observed with 6alpha-methyl prednisolone.

Conclusion: MRP2 is functionally active along with P-gp in effluxing drug molecules out of corneal epithelium. Steroids were able to significantly inhibit both P-gp and MRP2 mediated efflux of erythromycin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Absorption
  • Adrenal Cortex Hormones / pharmacology*
  • Adrenal Cortex Hormones / toxicity
  • Animals
  • Biological Transport / drug effects*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Epithelium, Corneal / cytology
  • Epithelium, Corneal / drug effects*
  • Epithelium, Corneal / metabolism
  • Erythromycin / pharmacokinetics*
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Rabbits
  • Up-Regulation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adrenal Cortex Hormones
  • Multidrug Resistance-Associated Proteins
  • Erythromycin