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C. Xiang, M. Batugo, E. Zhang, S. Vazquez, D. Gale; Corneal Permeability Assay Using Clonetics Human Corneal Epithelial Culture Model: Evaluation and Application for the Assessment of Prodrugs. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5794.
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© ARVO (1962-2015); The Authors (2016-present)
Topical instillation is a common route of drug delivery to anterior chamber of the eye, in which corneal absorption is considered as the predominant pathway. The corneal epithelium is the major barrier that limits drug transport. This study was conducted to evaluate if Clonetics Human Corneal Epithelial Culture Model (CHCE) provides a suitable in vitro model (1) to test drug permeation across cornea; and (2) to be used to evaluate prodrugs as a strategy to enhance ocular exposure.
CHCE, manufactured by Cambrex Bio Science, is a three-dimensional model of the human corneal epithelium. Atenolol, nadolol and metoprolol were used as marker compounds to assess transcellular permeability. Apparent permeability (Papp) values were obtained by determining concentration in the receiver side by LC/MS/MS. The reproducibility of the Papp values of marker compounds was evaluated. The Papp values in CHCE model were compared with the permeability parameters obtained using excised rabbit corneas. The permeability of an acid compound A and its isopropyl ester prodrug was tested in CHCE. Ocular PK studies after topical dosing of either the acid or the prodrug to rabbits were conducted to determine if prodrugs showing enhanced permeability in the CHCE model also produced higher concentrations of the acid in vivo in cornea, aqueous humor and iris/ciliary body (ICB).
CHCE model showed a relatively broad dynamic range of permeability between low and high permeability markers. The Papp values of atenolol, nadolol and metoprolol were 0.41 ± 0.061, 0.36 ± 0.05 and 14.28 ± 0.92 x 10-6 cm/sec, respectively. These values correlated well with the permeability obtained using excised rabbit corneas. Permeability of marker compounds using CHCE model were reproducible among the wells tested and between batches. The Papp values of the acid compound A was 0.2 x 10-6 cm/sec, suggesting low permeability. In contrast, the ester prodrug, hydrolyzed by corneal epithelium esterases into the acid, showed a much higher Papp value of 20.8 x 10-6 cm/sec for the acid. The acid exposure in cornea, aqueous humor and ICB increased dramatically after topical administration of the prodrug in rabbits.
This study demonstrated that CHCE model is a valuable tool to evaluate corneal permeability in vitro and to guide prodrug selection.
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