Mechanisms of corneal drug penetration. I: In vivo and in vitro kinetics.

Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that these compounds may have access to a diffusional channel for corneal transport is presented. In vitro permeability studies were also conducted in an effort to quantitate the corneal diffusion of compounds covering a range of molecular weights and partition coefficients; the results corresponded well with the results of in vivo experiments. Calculations of energies of activation, taken from Arrhenius plots, indicate that the diffusion of drug across the cornea may be by two different mechanisms that depend on the physical-chemical characteristics of the perfusant. One mechanism appears similar to drug movement in an aqueous environment and is characterized by an activation energy similar to that for diffusion in water. The other relates to the expected partitioning of a compound across cellular membranes represented by a relatively high activation energy for diffusion. For hyrdophilic compounds, the epithelium appears to be rate limiting to drug movement, whereas for hydrophobic compounds, the stroma is rate limiting. In the presence of calcium-chelating agents, glycerol demonstrated an increase in corneal penetration in vivo. This effect appears to be reversible at specific concentrations of chelator. In contrast, divalent cations reduced corneal penetration of glycerol. The known calcium chelator EDTA was shown to penetrate the cornea, conjunctiva, and iris/ciliary body from a topically applied dose. The implications of this observation pertain to toxicity effects when EDTA is incorporated into ocular drug products for stability purposes, or novel stratagems for improving ocular bioavailability of topically applied drugs are employed. The addition of calcium-chelating agents to in vivo mounted corneas demonstrated increases in permeability of the cornea to glycerol which were directly related to the concentration of chelating agent used. These results paralleled the findings of similar in vivo studies. The results of these studies are consistent with a currently proposed 'pore' model for the penetration of drugs through the cornea which demonstrates both a partition coefficient and molecular weight dependency on the permeability of the cornea to transported compounds.