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Ashutosh A. Kulkarni, William Chang, Jie Shen, Devin Welty; Use of Clonetics® Human Corneal Epithelial Cell Model for Evaluating Corneal Penetration and Hydrolysis of Ophthalmic Drug Candidates. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3259.
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The Clonetics® human corneal epithelial cell (cHCEC) culture provides a useful in vitro model for assessing the corneal penetration of ophthalmic drug candidates and to elucidate the effects of formulation on the permeability of drug candidates. We further assessed the utility of this model by generating in vitro-in vivo correlation (IVIVC) for compounds with different chemical templates and with a wide range of corneal permeability values. In addition, we also evaluated the ability of these cells to potentially hydrolyse ester prodrugs.
In vitro formulation screening studies were conducted for 5 compounds using the cHCEC model. The cells were monitored for transepithelial electrical resistance (TEER) values before and after treatment to assess integrity of the cell layer throughout the course of the study. The in vitro permeability results were correlated to dose normalized maximal concentrations (Cmax/dose) of the compounds in rabbit aqueous humor following topical administration in vivo. All analytes, including the hydrolysis product (metabolite) of ester prodrugs, were measured by LC-MS/MS.
All cells used in the permeability studies had pre-treatment TEER ≥ 500 ohm·cm2 confirming the integrity of the cell layer. The apparent in vitro corneal permeability of the 5 compounds ranged from 0.087 X 10-6 - 7.89 X 10-6 cm/s (n=3). The corresponding dose normalized maximal concentration in rabbit aqueous humor (Cmax/dose) exhibited good correlation with the in vitro corneal permeability values (r2 = 0.79). Furthermore, the ester prodrugs were efficiently hydrolysed by cHCEC.
Good IVIVC for compounds with different chemical templates and a wide range of corneal permeability values and the ability to hydrolyse ester prodrugs further strengthens the utility of cHCEC for in vitro formulation screening of ophthalmic drug candidates.
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