Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement

Pharm Res. 2009 May;26(5):1261-9. doi: 10.1007/s11095-008-9730-0. Epub 2008 Oct 7.


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,+) 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,+)) 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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyclovir / chemistry
  • Acyclovir / pharmacokinetics*
  • Amino Acid Transport Systems / metabolism*
  • Animals
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacokinetics*
  • Biological Transport
  • Cornea / metabolism*
  • Drug Stability
  • Esters / chemistry
  • Esters / pharmacokinetics
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics*
  • Rabbits
  • Solubility


  • Amino Acid Transport Systems
  • Esters
  • Prodrugs
  • Aspartic Acid
  • Acyclovir