Metabolic and Permeation Barriers to the Ocular Absorption of Topically Applied Enkephalins in Albino Rabbits

ABSTRACT

The objective of this study was to test the hypothesis that there existed substantial metabolic and permeation barriers to the ocular absorption of topically applied peptides in the albino rabbit. Leucine enkephalin, methionine enkephalin, and [D-ala²]-met-enkephalinamide were used as model peptides, while radiotracer techniques were used as the analytical methodology. The corneal epithelium was found to offer considerable resistance to the permeation of these peptides from tears into aqueous humor, as evidenced by the 1% or less of topical dose absorbed and by a 14 fold improvement in the amount of peptide absorbed upon removing the corneal epithelium prior to solution instillation. The metabolic barrier, believed to be composed of aminopeptidases and other peptidases, was also substantial in that less than 1% and 13% of the methionine and leucine enkephalins absorbed, respectively, remained intact. Unfortunately, this barrier was not perturbed appreciably by pretreating the eye with bestatin, an aminopeptidase inhibitor. Results obtained with [D-ala²]-metenkephalinamide suggest that a more practical strategy to circumvent this metabolic barrier is to administer metabolically stable peptide analogs.