Abstract
Purpose :
Determine the ocular distribution of orally administered multifunctional antioxidants (MFAOs) along with their monofunctional and parent analogs in the eyes of rats and determine whether the molecular attributes of these compounds can be correlated with their ocular distribution.
Methods :
Twenty-four compounds consisting of 6 MFAOs, their monofunctional analogs and nonfunctional parent compounds were incorporated into standard rat chow (0.05%) and orally administered to Sprague Dawley rats. After 7 days of feeding, all rats were terminally perfused with PBS and their eyes removed and further dissected for drug level quantification of the cornea, iris/ciliary processes, lens, neural retina, and retinal pigment epithelium attached to the remaining posterior segment by HPLC-MS. Drug levels were correlated with molecular parameters calculated using Molecular Orbital Environment (MOE) which included atomic polarizabilities, molecular refractivity, logP, topological polar surface area, kappa shape indices, Balaban’s 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.
Results :
Several correlations were observed between ocular drug concentrations versus calculated MOE molecular parameters. The HK-piperidine with R2 = methoxy and the HK-pyrrolidine with R2 = hydrogen MFAOs were generally shown to accumulate in greater quantities relative to their parent and monofunctional analogs. The JHX-series with R2 = methoxy or hydrogen, the HK-piperidine with R2 = hydrogen, and the HK-pyrrolidine with R2 = methoxy showed greater accumulation of either free radical scavenger or metal chelator monofunctional analog compared to the parent or multifunctional analogs.
Conclusions :
Results to date suggest that quantitative structure activity relation (QSAR) studies that correlate the ocular levels of MFAOs and their analogs with in silico MOE calculated molecular parameters have merit in helping us understand the distribution of these drugs in the eye.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.