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 (12.1 +/- 1.48 x 10(-6) cm/s) was fourfold higher than D-Asp-ACV (3.12 +/- 0.36 x 10(-6) cm/s) and ACV (3.25 +/- 0.56 x 10(-6) cm/s). 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,B-+ and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66 +/- 0.21 x 10(-6) cm/s. 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,B-+) 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).