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

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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 (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 pKa and logP values for both prodrugs were identical. Transcorneal permeability of l-Asp-ACV \(\left( {{\text{12}}{\text{.1}} \pm {\text{1}}{\text{.48}} \times {\text{10}}^{ - {\text{6}}} {{{\text{cm}}} \mathord{\left/ {\vphantom {{{\text{cm}}} {\text{s}}}} \right. \kern-\nulldelimiterspace} {\text{s}}}} \right)\) was fourfold higher than d-Asp-ACV \(\left( {{\text{3}}{\text{.12}} \pm {\text{0}}{\text{.36}} \times {\text{10}}^{ - {\text{6}}} {{{\text{cm}}} \mathord{\left/ {\vphantom {{{\text{cm}}} {\text{s}}}} \right. \kern-\nulldelimiterspace} {\text{s}}}} \right)\) and ACV \(\left( {{\text{3}}{\text{.25}} \pm {\text{0}}{\text{.56}} \times {\text{10}}^{ - {\text{6}}} {{{\text{cm}}} \mathord{\left/ {\vphantom {{{\text{cm}}} {\text{s}}}} \right. \kern-\nulldelimiterspace} {\text{s}}}} \right)\). 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 B0,+ and L amino acid transporter inhibitor, decreased transcorneal l-Asp-ACV permeability to \({\text{2}}{\text{.66}} \pm {\text{0}}{\text{.21}} \times {\text{10}}^{ - {\text{6}}} {{{\text{cm}}} \mathord{\left/ {\vphantom {{{\text{cm}}} {\text{s}}}} \right. \kern-\nulldelimiterspace} {\text{s}}}\). 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 B0,+) 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).

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Acknowledgement

This project was supported by NIH grant numbers P20RR021929, from the National Center for Research Resources, and EY018426-01 from the National Eye Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Faser Hall, University, Mississippi, 38677, USA

    Soumyajit Majumdar, Tushar Hingorani, Ramesh Srirangam & Michael A. Repka

  2. Research Institute of Pharmaceutical Sciences, The University of Mississippi, University, Mississippi, 38677, USA

    Soumyajit Majumdar, John M. Rimoldi & Michael A. Repka

  3. Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, Mississippi, 38677, USA

    Soumyajit Majumdar, Rama Sarma Gadepalli & John M. Rimoldi

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Electronic supplementary material

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Fig. S-1

Proton NMR (500 MHz) of l-Asp-ACV in DMSO (DOC 299 KB)

Fig. S-2

Proton NMR (500 MHz) of d-Asp-ACV in DMSO (DOC 81 KB)

Fig. S-3

13C NMR of l-Asp-ACV in DMSO (DOC 181 KB)

Fig. S-4

13C DEPT NMR of d-Asp-ACV in DMSO (DOC 75.5 KB)

Fig. S-5

13C NMR of d-Asp-ACV (DOC 88.5 KB)

Fig. S-6

Proton NMR of intermediate compound (3l-Ester of ACV) (DOC 184 KB)

Fig. S-7

Proton NMR of intermediate compound (3d-Ester) (DOC 78.5 KB)

Fig. S-8

13C NMR of intermediate compound (3l-ester) (DOC 82 KB)

Fig. S-9

13C NMR of intermediate compound (3d-ester) in DMSO (DOC 79 KB)

Fig. S-10

13C DEPT NMR of intermediate compound (3d-ester) in DMSO (DOC 78 KB)

Fig. S-11

LC-MS data for d-Asp-ACV and l-Asp-ACV (DOC 518 KB)

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Majumdar, S., Hingorani, T., Srirangam, R. et al. Transcorneal Permeation of l- and d-Aspartate Ester Prodrugs of Acyclovir: Delineation of Passive Diffusion Versus Transporter Involvement. Pharm Res 26, 1261–1269 (2009). https://doi.org/10.1007/s11095-008-9730-0

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  • DOI: https://doi.org/10.1007/s11095-008-9730-0

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