IOVS British Journal of Pharmacology
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(Investigative Ophthalmology and Visual Science. 2006;47:287-294.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0189
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Characterization of Brimonidine Transport in Retinal Pigment Epithelium

Ning Zhang,1 Ram Kannan,2,3,4 Curtis T. Okamoto,1 Stephen J. Ryan,4 Vincent H. L. Lee,1,2 and David R. Hinton2,3,4

1From the Departments of Pharmaceutical Sciences, 2Ophthalmology, and 3Pathology and the 4Doheny Eye Institute, School of Pharmacy and Keck School of Medicine, University of Southern California, Los Angeles, California.

PURPOSE. To investigate the involvement of carrier-mediated transport mechanisms in brimonidine transport in retinal pigment epithelium (RPE).

METHODS. The transport of [3H]-brimonidine in bovine RPE-choroid explants was evaluated in a modified Ussing chamber. The uptake of [3H]brimonidine was evaluated in differentiated ARPE-19 cells cultured on permeable transwell filters.

RESULTS. The transport of brimonidine into (choroid-to-retina transport [inward]) and out of (retina-to-choroid transport [outward]) the eye in bovine RPE-choroid explants was temperature dependent. Both inward and outward brimonidine transport decreased at 5 µM compared with 10 nM. The melanin pigmentation of RPE did not significantly affect tissue permeability at either brimonidine dose. A saturable component was identified for the inward transport with the apparent Michaelis-Menten constant and a maximum transport rate of 51 µM and 148 pmol/(cm2·h), respectively. Both apical (representing retina-to-choroid transport) and basolateral (representing choroid-to-retina transport) brimonidine uptake in ARPE-19 cells showed temperature dependence. Apical uptake was higher than basolateral uptake at 37°C and was decreased to 70% in the presence of NaN3 or in the absence of extracellular Na+. Besides {alpha}2-agonists, apical uptake was inhibited by verapamil, desipramine, and quinidine, but not by MPP+ (1-methyl-4-phenylpyridinium), TEA (tetraethylammonium), decynium-22, carnitine, PHA (p-aminohippurate), alanine, or inosine. Basolateral brimonidine uptake increased by 35% at extracellular pH of 6 and decreased by 50% under cell-depolarized conditions of high medium K+ and 1 µM valinomycin. Temperature-dependent components of basolateral uptake were not saturated at doses up to 2 mM.

CONCLUSIONS. A carrier-mediated transport process for brimonidine in RPE was demonstrated in bovine RPE-choroid explants and polarized ARPE-19 cells. This transport system may play a significant role in modulating the movement of brimonidine into and out of the eye.






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