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Enhanced Corneal Absorption of Erythromycin by Modulating P-Glycoprotein and MRP Mediated Efflux with Corticosteroids

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Abstract

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, AUC0 − ∞, C max and C last values of erythromycin, observed with 6α-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.

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Abbreviations

AP:

apical

AUC:

area under curve

BL:

basolateral

CsA:

cyclosporine A

Ery:

erythromycin

MDCK:

Madin-Darby Canine Kidney

MPL:

6α-methyl prednisolone

MRP:

multidrug resistance associated protein

P app :

apparent permeability

P-gp:

P-glycoprotein

PL:

prednisolone

PS:

prednisone

rPCEC:

rabbit primary corneal epithelial cell

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Acknowledgements

This work was supported by NIH grants R01EY09171-14 and R01EY10659-12

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Authors and Affiliations

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

    Sudharshan Hariharan, Sriram Gunda, Gyan P. Mishra, Dhananjay Pal & Ashim K. Mitra

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  1. Sudharshan Hariharan
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  2. Sriram Gunda
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Correspondence to Ashim K. Mitra.

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Hariharan, S., Gunda, S., Mishra, G.P. et al. Enhanced Corneal Absorption of Erythromycin by Modulating P-Glycoprotein and MRP Mediated Efflux with Corticosteroids. Pharm Res 26, 1270–1282 (2009). https://doi.org/10.1007/s11095-008-9741-x

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  • DOI: https://doi.org/10.1007/s11095-008-9741-x

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