Drug Flux Across RPE Cell Models: The Hunt for An Appropriate Outer Blood-Retinal Barrier Model for Use in Early Drug Discovery.

Eva Ramsay,Laura Hellinen,Heli Skottman,Kai Kaarniranta,Heidi Hongisto,Marika Ruponen,Kati-Sisko Vellonen,Eva Ramsey

doi:10.3390/pharmaceutics12020176

Eva Ramsay, Laura Hellinen + Show 6 more

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https://doi.org/10.3390/pharmaceutics12020176

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Abstract

The retinal pigment epithelial (RPE) cell monolayer forms the outer blood–retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of several RPE secondary cell lines (ARPE19, ARPE19mel, and LEPI) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow Papp value range, with relatively high permeation rates (5.2–26 × 10−6 cm/s. In contrast, hESC-RPE and LEPI cells efficiently restricted the drug flux, and displayed even lower Papp values than those reported for bovine RPE-choroid, with the range of 0.4–32 cm−6/s (hESC-RPE cells) and 0.4–29 × 10−6 cm/s, (LEPI cells). Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE and LEPI cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, LEPI and hESC-RPE cells are valuable tools in ocular drug discovery.

Highlights

The retinal pigment epithelium (RPE) located in the posterior eye between the neural retina and choroidal circulation is essential for vision [1]
We present the permeation characteristics of nine small molecular-weight drugs with varying lipophilicities across ARPE19, ARPE19mel, LEPI, human fetal RPE cells (hfRPE), and hESC-RPE cell monolayers
A wide range of Papp values was observed in LEPI (0.4–29 × 10−6 cm/s) and hESC-RPE (0.4–32 × 10−6 cm/s) cells, similar to what was previously found in the bovine RPE-choroid that displayed Papp values for these drugs ranging from 1.4 to 69.2 × 10−6 cm/s (Figure 1A,B) [2]

Summary

Introduction

The retinal pigment epithelium (RPE) located in the posterior eye between the neural retina and choroidal circulation is essential for vision [1]. The RPE forms the outer blood-retinal barrier by forming tight junctions between the cells. This restricting barrier prevents the entry of xenobiotics into the eye, and clinically useful drugs from the systemic blood circulation. The passage of drugs from the systemic circulation is restricted by the RPE, and only compounds with a high potency and/or selective targeting or a very wide therapeutic window can be administered systemically to treat retinal disorders. Especially age-related macular degeneration, are becoming more common as the population ages [4]. These diseases represent a major burden for healthcare systems and discomfort for the patients. Ocular drug development against these retinal diseases is an area in which there is extensive research, but these programs demand reliable animal, tissue, and cell models, in order to improve the clinical relevance of early drug development

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