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Peter F Kador, Hiroyoshi Kawada, Karen Blessing; Molecular Physicochemical Parameters Associated With Drug Uptake For The Lens And Retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5249.
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© ARVO (1962-2015); The Authors (2016-present)
While animal studies suggest that multifunctional antioxidants for treating lens and neural retina changes associated with cataracts and AMD are beneficial, their routes of drug delivery to the lens and retina after oral administration are significantly different. The purpose of this study was to identify molecular parameters required to target multifunctional antioxidants to the lens versus retina.
Twenty four compounds possessing the 2-amino-1,3-pyrimidine ring system with/without a 5-hydroxyl group and/or carbonyl groups adjacent to the 2-amine were synthesized. Compounds were incorporated into chow (0.05%) and orally administered to C57BL/6 mice. After 14 days of feeding, all mice were perfused with PBS, the lens and neural retina were removed, and the drug levels were quantified by HPLC-MS. Drug levels were correlated with molecular parameters calculated using MOE. These included atomic polarizabilities, molecular refractivity, logP, topological polar surface area, kappa shape indices; Balaban’s connectivity topological index, dipole moment; surface area, volume, shape, water accessible surface area, hydrophilic/hydrophobic volume, polar volume, critical packing parameter , hydrophilic-lipophilic descriptors, water accessible surface area of all hydrophobic/polar atoms, and positive/negative charge weighted surface areas.
In the lens, positive correlations were observed between the drug accumulation and topological polar surface area, Balaban’s connectivity topological index, hydrophilic volume, and fractional water accessible surface area (p < 0.05) while negative correlations were observed between critical packing parameter (p < 0.01), and fractional water accessible surface area of all hydrophobic/polar atoms (p < 0.05). In the retina, correlations similar to the lens were observed with Balaban’s connectivity topological index and hydrophilic volume, but negative correlations were observed with critical packing parameter (p < 0.01) and water accessible surface area of all hydrophobic/polar atoms.
In the series of compounds examined, correlations suggest that increasing molecular hydrophilicity and polar surface areas, and decreasing hydrophobicity affect drug accumulation into the lens and retina.
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