Rate limiting barrier to the penetration of ocular hypotensive beta blockers across the corneal epithelium in the pigmented rabbit.

The objective of this study was to determine the rate-limiting layer(s) in the penetration of ocular hypotensive beta blockers across the corneal epithelium in the pigmented rabbit. The beta blockers studied were, in order of increasing lipophilicity, atenolol, timolol, levobunolol, and betaxolol. Corneal drug penetration was evaluated over 240 min using the isolated pigmented rabbit cornea in the modified Ussing chamber. Reversed phase HPLC was the analytical methodology. The cornea was preexposed to 20-100 microM digitonin for 15 min in an attempt to strip off selective layers of the corneal epithelium. The corneal epithelium offered no resistance to the penetration of the very lipophilic betaxolol. The major resistance to the corneal penetration of the moderately lipophilic timolol and levobunolol was in the superficial cell layers of the corneal epithelium. For the hydrophilic atenolol, the resistance to corneal drug penetration appeared to extend across all corneal epithelial cell layers. The above findings suggest that the number of corneal epithelial cell layers limiting the corneal penetration of ocularly administered drugs is inversely related to drug lipophilicity.