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

Sudharshan Hariharan1, Sriram Gunda, Gyan P Mishra

  • 1Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.

Pharmaceutical Research
|October 30, 2008
PubMed
Abstract

Insights

Multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) actively transport drugs from the corneal epithelium. Corticosteroids effectively inhibit this efflux, enhancing drug delivery to the eye.

Area of Science:

  • Ocular pharmacology
  • Drug transport mechanisms
  • Corneal epithelial biology

Background:

  • The corneal epithelium acts as a barrier, limiting drug penetration into the eye.
  • Efflux transporters like P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) contribute to drug efflux from corneal cells.
  • Understanding these transporters is crucial for optimizing ophthalmic drug delivery.

Purpose of the Study:

  • To investigate the in vivo functional activity of MRP2 in rabbit corneal epithelium.
  • To assess the impact of corticosteroids on P-gp and MRP2-mediated efflux of erythromycin.
  • To evaluate the potential of corticosteroids to enhance ocular drug penetration.

Main Methods:

  • Utilized cultured rabbit primary corneal epithelial cells (rPCECs) as an in vitro model.
  • Conducted bidirectional transport studies using Madin-Darby Canine Kidney (MDCK) cells overexpressing P-gp (MDR1) and MRP2.
  • Performed ocular pharmacokinetic studies in rabbits with erythromycin, inhibitors, and corticosteroids.

Main Results:

  • Erythromycin demonstrated substrate characteristics for both P-gp and MRP2, indicated by differential permeability across MDCK cells.
  • Steroids significantly inhibited erythromycin cellular accumulation in rPCECs in a dose-dependent manner.
  • In vivo, corticosteroids inhibited P-gp and MRP2-mediated efflux, increasing erythromycin's pharmacokinetic parameters (ka, AUC, Cmax, Clast), with 6α-methylprednisolone showing the greatest effect.

Conclusions:

  • MRP2 is functionally active in the corneal epithelium, working alongside P-gp to efflux drugs.
  • Corticosteroids effectively inhibit the efflux activity of both P-gp and MRP2.
  • This inhibition by corticosteroids suggests a potential strategy to improve ocular drug bioavailability.

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