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Aapo Tervonen, Iina Vainio, Soile Nymark, Jari AK Hyttinen; Prediction of Passive Permeability across the Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1881.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal pigment epithelium (RPE) is an important part of the normal visual cycle. Located behind the retina, one of its main functions as a part of the blood-retinal barrier is to regulate the transport between the retina and systemic blood circulation. The barrier properties, and changes in them, have a role in certain retinal diseases, such as age-related macular degeneration (AMD). Previously, mostly pharmacokinetic compartmental models have been proposed to model the RPE barrier properties. In this study, we introduce for the first time, an accurate physical structure-based model of passive permeability across the RPE.
Our model relates the permeability coefficients of RPE structures to the physicochemical properties of materials forming the RPE. Our model structure bases on a corneal diffusion model by Edwards, A. et al. (Pharm Res 18: 1497-508, 2001). Transcellular and paracellular diffusion components are described by separate permeability equations based on the material properties of each pathway and the basic interactions between each of them and the characteristics of the diffusing molecule, such as radius and lipophilicity. Transcellular pathway is further divided into pathways traversing the cell cytoplasm and diffusing laterally within the cell membrane. The improved structure of our tight junction (TJ) model takes into account both the pore pathway for small molecules and the leak pathway for large molecules.
Our RPE model is able to predict correct magnitude for the molecular permeabilities and its behaviour corresponds to experimental results. The results show that the paracellular pathway is the dominant pathway, the transcellular pathway becoming more permeable with small and lipophilic molecules. Further, the permeability magnitude and behaviour of the TJ model appear similar to the experimental data of molecules mainly traversing through the TJs.
RPE barrier models would facilitate novel drug development against retinal diseases. Our model forms, to our knowledge, the mot advanced platform for development and refinements of diffusional models of RPE and it can be used e.g. to study the pathogenesis of AMD. Further, our model combines our knowledge of the RPE structure and permeability. However, due to the inconsistent experimental data of RPE permeability, rigorous validation of this type of computational models cannot be made.
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