Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity.
OBJECTIVE
To determine the effects of solute molecular weight and lipophilicity on the permeability of a retinal pigment epithelium (RPE)-choroid preparation.


METHODS
Fresh RPE-choroid specimens from bovine eyes were placed in diffusion chambers for permeability experiments with carboxyfluorescein, fluorescein isothiocyanate (FITC)-labeled dextrans with molecular masses from 4 to 80 kDa, and beta-blockers exhibiting a wide range of lipophilicity (atenolol, nadolol, pindolol, timolol, metoprolol, and betaxolol). Permeability experiments were performed both in the choroid-to-retina (inward) direction and in the retina-to-choroid (outward) direction. Carboxyfluorescein and FITC-dextrans were determined by fluorometry, and beta-blockers by HPLC. The transepithelial electrical resistance and potential difference were monitored during the experiments.


RESULTS
Permeability of the fluorescent FITC-dextran probes through RPE-choroid decreased significantly with the increasing size of the probe. RPE-choroid was 35 times more permeable to carboxyfluorescein (376 Da) than to FITC-dextran 80 kDa. The permeabilities of lipophilic beta-blockers were up to 8 and 20 times higher than that of hydrophilic atenolol and carboxyfluorescein, respectively. The lag time of solute flux across the RPE-choroid increased with the molecular weight and lipophilicity. Compared with published data on isolated sclera, bovine RPE-choroid was 10 to 100 times less permeable to hydrophilic compounds and macromolecules. The permeability of lipophilic molecules in RPE-choroid was in the same range as in the sclera.


CONCLUSIONS
RPE is a major barrier and may be the rate-limiting factor in the retinal delivery of hydrophilic drugs and macromolecules through the transscleral route. For lipophilic molecules, RPE-choroid, and sclera are approximately equal barriers.
Pitkänen
Leena
L
Department of Pharmaceutics, University of Kuopio, FIN-70211 Kuopio, Finland.
Ranta
Veli-Pekka
VP
Moilanen
Hanna
H
Urtti
Arto
A
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D002417:Cattle; D002829:Choroid / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003911:Dextrans / Q000493:pharmacokinetics*; D004058:Diffusion; D015194:Diffusion Chambers, Culture; D016503:Drug Delivery Systems; D004553:Electric Conductivity; D017097:Electric Impedance; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005452:Fluoresceins / Q000493:pharmacokinetics*; D015590:Fluorophotometry; D008970:Molecular Weight; D010539:Permeability; D010857:Pigment Epithelium of Eye / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D003911:Dextrans; D005452:Fluoresceins; C015219:fluorescein isothiocyanate dextran; C024098:6-carboxyfluorescein; D016650:Fluorescein-5-isothiocyanate