Ocular pharmacokinetic modeling using corneal absorption and desorption rates from in vitro permeation experiments with cultured corneal epithelial cells.

Purpose: To determine corneal absorption and desorption rate constants in a corneal epithelial cell culture model and to apply them to predict ocular pharmacokinetics after topical ocular drug application.

Method: In vitro permeation experiments were performed with a mixture of six beta-blockers using an immortalized human corneal epithelial cell culture model. Disappearance of the compounds from the apical donor solution and their appearance in the basolateral receiver solution were determined and used to calculate the corneal absorption and desorption rate constants. An ocular pharmacokinetic simulation model was constructed for timolol with the Stella program using the absorption and desorption rate constants and previously published in vivo pharmacokinetic parameters.

Results: The corneal absorption rates of beta-blockers increased significantly with the lipophilicity of the compounds. The pharmacokinetic simulation model gave a realistic mean residence time for timolol in the cornea (57 min) and the aqueous humor (90 min). The simulated timolol concentration in the aqueous humor was about 1.8 times higher than the previously published experimental values.

Conclusions: The simulation model gave a reasonable estimate of the aqueous humor concentration profile of timolol. This was the first attempt to combine cell culture methods and pharmacokinetic modeling for prediction of ocular pharmacokinetics. The wider applicability of this approach remains to be seen.