Transcorneal Permeation of l- and d-Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement

PURPOSE: The aim of this study was to evaluate the contribution of amino acid transporters in the transcorneal permeation of the aspartate (Asp) ester acyclovir (ACV) prodrug. METHODS: Physicochemical characterization, solubility and stability of acyclovir L: -aspartate (L: -Asp-ACV) and acyclovir D: -aspartate (D: -Asp-ACV) were studied. Transcorneal permeability was evaluated across excised rabbit cornea. RESULTS: Solubility of L: -Asp-ACV and D: -Asp-ACV were about twofold higher than that of ACV. The prodrugs demonstrated greater stability under acidic conditions. Calculated pK(a) and logP values for both prodrugs were identical. Transcorneal permeability of L: -Asp-ACV [Formula: see text] was fourfold higher than D: -Asp-ACV [Formula: see text] and ACV [Formula: see text]. ACV generation during the transport process was minimal. L: -Asp-ACV transport was sodium and energy dependent but was not inhibited by glutamic acid. Addition of BCH, a specific B(0,+) and L amino acid transporter inhibitor, decreased transcorneal L: -Asp-ACV permeability to [Formula: see text]. L: -Asp-ACV and D: -Asp-ACV did not demonstrate significant difference in stability in ocular tissue homogenates. CONCLUSION: The results demonstrate that enhanced transport of L: -Asp-ACV is as a result of corneal transporter involvement (probably amino acid transporter B(0,+)) and not as a result of changes in physicochemical properties due to prodrug derivatization (permeability of D: -Asp-ACV and ACV were not significantly different).