Corneal penetration behavior of beta-blocking agents II: Assessment of barrier contributions.

Rabbit corneas were excised and mounted in a chamber to determine the permeability characteristics of a group of beta-blocking agents. By measuring the permeability rate of each drug across intact cornea, stroma alone, epithelium-stroma, and stroma-endothelium, it was possible to determine the resistance to penetration for each corneal layer. The reciprocal of the sum of resistances for the epithelium, stroma, and endothelium equaled the experimentally determined permeability coefficient for the intact cornea (104 +/- 6.0%). Thus, the penetration of beta-blocking agents through the excised rabbit cornea could be treated as three barriers in series. For hydrophilic compounds, the epithelium was the rate-determining barrier. The endothelium offered less resistance, whereas the stroma offered only very minimal resistance. The lipophilic compounds penetrated the excised cornea more rapidly. However, the stroma became rate-determining for the most lipophilic compounds (penbutolol, bufuralol, bevantolol, and propranolol). Although the octanol-buffer (pH 7.65) distribution coefficient of these compounds varied over a fourfold logarithmic range, the permeability coefficient was considered nearly constant [3.4 X 10(-5) (+/- 0.34) cm/sec] for stroma. Also, the ratios of tortuosity to porosity for the stromal layer were 1.58 +/- 0.15. These results suggest that drug diffuses through an aqueous media of gel-like mucopolysaccharide interspersed by a matrix of collagen fibrils. From further analyses intra- and intercellular pathways for epithelium and endothelium were added to the model resulting in a sigmoidal representation of permeability coefficient versus distribution coefficient. However, the intercellular (pore) pathway could not be adequately quantified because of the variation in the data for very hydrophilic compounds.