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

Abstract

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 (LAsp-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 2-fold 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±1.48×10 −6 cm/s) was 4-fold higher than D-Asp-ACV (3.12±0.36×10 −6 cm/s) and ACV (3.25±0.56×10 −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 o,+ and L amino acid transporter inhibitor, decreased transcorneal L-Asp-ACV permeability to 2.66±0.21×10 −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,+ ) 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).

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

“…Glycine concentrations in the neural retina is 5-fold higher than in the plasma (Okamoto et al, 2009), and glycine accumulates in the retina because of the highly concentrative capacity of ATB 0,+ and glycine transporters (Ganapathy and Ganapathy, 2005;Okamoto et al, 2009). Results observed in our study are supported by earlier preclinical studies, which showed the involvement ATB 0,+ in the transport of amino acid prodrugs of acyclovir and L-arginine across rabbit cornea (Jain-Vakkalagadda et al, 2004;Majumdar et al, 2009).…”

Excised Porcine Cornea Integrity Evaluation in an in vitro Model of Iontophoretic Ocular Research

“…Because of the poor availability of human donor corneas for experimental purposes, in vitro studies are largely performed using excised corneal tissues from laboratory animals [11] . However, the sacrifice of animals for in vitro experimental purposes has been deemed inappropriate.…”

Nonpolymeric nanoassemblies for ocular administration of acyclovir: Pharmacokinetic evaluation in rabbits

“…We selected a prodrug that would increase the lipophilic character of acyclovir, optimizing its permeation through the cornea, and simultaneously the appropriate nanotechnology to provide prolonged release of acyclovir at the absorption site. Each of these approaches has been widely studied: macromolecular complex, amino acid ester, and dipeptide prodrugs of acyclovir were found to be more stable, more soluble, and capable of improving the bioavailability of ACV after oral and ocular administration [17], [19], [20], [21], [38] and [39], and colloidal carriers have been widely exploited to enhance corneal permeation, control drug release at the absorption site, and obtain a selective target of acyclovir [35], [40] and [41].…”