The rates of corneal penetration and efflux of phenylephrine (PE) and its metabolites were found to be limited by the epithelium. The rate constant for corneal penetration as measured in a lucite block perfusion system was 1.06 X 10(-3) hr-1 when the epithelium was present and 1.25 X 10(-2) hr-1 when the epithelium was denuded. Epithelial removal reduced the half-time (t1/2) for corneal efflux of PE from 24 min to 6 min. Ocular absorption of topically applied 0.1% PE (three 30-microliters instillations at five-minute intervals) was increased when the corneal epithelium was removed prior to application. Corneal concentrations of PE increased threefold, aqueous humor concentrations increased ten to 13-fold and iris/ciliary body concentrations increased sixfold upon epithelial removal. HPLC analysis suggested that the corneal epithelium was responsible for the metabolic degradation of PE, which occurred following topical instillation of PE.