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Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations.

AbstractPURPOSE:
The aim of this study was to evaluate a series of dipeptide monoester ganciclovir (GCV) prodrugs with the goal of improving ocular bioavailability of GCV from topical ophthalmic solutions.
METHODS:
Solubility, logP, pH-stability profile, permeability, interaction with corneal peptide transporter, and in vivo efficacy against herpes simplex virus type 1 (HSV-1) ocular disease in the rabbit model were studied.
RESULTS:
Val-Val-GCV, Tyr-Val-GCV, and Gly-Val-GCV were more stable in aqueous solution than Val-GCV, showing no measurable degradation even after 7 d at 37 degrees C, within the pH range of 1.4-5.4. Tyr-Val-GCV and Val-Tyr-GCV were the most lipophilic among the prodrugs synthesized and were predicted to have an n-octanol/water partition coefficient 33 times greater than that of GCV. All of the prodrugs had a much higher aqueous solubility than the parent drug. Transcorneal permeability of Val-GCV and Val-Val-GCV was seven- to eightfold greater than that of GCV, in the presence of a proton gradient, and was significantly decreased in the presence of Gly-Pro. Val-Val-GCV (1% w/v) provided significantly better therapeutic activity than trifluorothymidine (1% w/v) against HSV-1 epithelial keratitis and equivalent therapeutic activity against stromal keratitis in the rabbit eye model.
CONCLUSIONS:
Val-Val-GCV demonstrates excellent corneal permeability and chemical stability, high aqueous solubility, and substantial in vivo antiviral activity against the HSV-1.
AuthorsSoumyajit Majumdar, Yasser E Nashed, Kunal Patel, Ritesh Jain, Motoki Itahashi, Donna M Neumann, James M Hill, Ashim K Mitra
JournalJournal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 21 Issue 6 Pg. 463-74 (Dec 2005) ISSN: 1080-7683 [Print] United States
PMID16386088 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Dipeptides
  • Esters
  • Ophthalmic Solutions
  • Prodrugs
  • Ganciclovir
Topics
  • Animals
  • Antiviral Agents (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Biological Availability
  • Biological Transport
  • Chromatography, High Pressure Liquid
  • Corneal Stroma (drug effects, metabolism, virology)
  • Dipeptides (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Drug Stability
  • Epithelium, Corneal (drug effects, metabolism, virology)
  • Esters
  • Ganciclovir (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)
  • Herpesvirus 1, Human (drug effects)
  • Instillation, Drug
  • Keratitis, Herpetic (drug therapy, virology)
  • Male
  • Molecular Structure
  • Ophthalmic Solutions
  • Permeability
  • Prodrugs (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
  • Rabbits
  • Solubility

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