Transport of acyclovir ester prodrugs through rabbit cornea and SIRC-rabbit corneal epithelial cell line

The purpose of this study is to assess the permeability of acyclovir (ACV) prodrugs through the rabbit corneal cell line (SIRC) as well as the cornea, and characterize the SIRC cell line for transport and metabolism studies o f ester prodrugs. Prodrug derivatization of an acycloguanosine antiviral ag ent, acyclovir, was employed to improve its permeability across the cornea. New Zealand albino rabbits were used as an animal model for corneal studie s. The SIRC cell line grown on polyester membranes was used for transport o f these prodrugs. SIRC cells grown on the membrane support for 10 days deve loped four to six layers of epithelial cells, and this is comparable to the normal rabbit corneal epithelial layer. Transport experiments were conduct ed across the rabbit cornea and confluent SIRC cells using side-by-side dif fusion-cell apparatus. Enzymatic hydrolysis of these compounds was evaluate d in SIRC cell lysates. Appropriate reversed phase HPLC method(s) were empl oyed for quantitation of both the prodrug and ACV simultaneously. Corneal p ermeabilities of some of these prodrugs (Malonyl ACV and Acetyl ACV) were h igher relative to ACV. The SIRC cell line permeability values of all the pr odrugs were higher compared to that of the intact cornea. The total amount of ACV-prodrugs transported, i.e., unhydrolyzed prodrugs and regenerated AC V, across the SIRC cell line was more relative to ACV. Hydrolytic studies i n the SIRC cell line homogenate demonstrated the bioreversion potential of the prodrugs and the presence of enzymes, particularly the cholinesterase i n the SIRC cell line, It may be concluded that the SIRC cell line is leakie r compared to the cornea. Keeping in mind the limitations, the SIRC cell li ne after further characterization may be used for transport and metabolism studies of ester prodrugs. (C) 2001 Wiley-Liss, Inc. and the American Pharm aceutical Association.