Topically administered cannabinoids have been shown to reduce intraocular pressure by interacting with the ocular cannabinoid receptor. Most cannabinoids have very poor aqueous solubility, which limits their pharmaceutical development and usefulness. In this study, permeation of three cannabinoids (arachidonylethanolamide, R-methanandamide and noladin ether) and their water-soluble phosphate ester prodrugs across isolated rabbit cornea was investigated in vitro. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was used to solubilize the parent cannabinoids in permeation studies to achieve the required concentration in donor and receiving cells. Highest fluxes were obtained with lipophilic parent compounds administered with HP-beta-CD, and the fluxes of phosphate esters were 45-70% that of their corresponding parent compounds. Phosphate esters hydrolysed on the surface of the cornea or during the permeation to release the lipophilic parent compound, which further permeated the cornea. No phosphate esters were detected on the endothelial side of the cornea. Although the phosphate esters had lower fluxes than their corresponding parent compounds in these HP-beta-CD formulations, the results are promising and the fluxes of phosphate esters are significantly higher than the fluxes of parent compounds administered as a suspension (due to their low aqueous solubility) without HP-beta-CD.