Abstract | PURPOSE: 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.
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Authors | Soumyajit Majumdar, Yasser E Nashed, Kunal Patel, Ritesh Jain, Motoki Itahashi, Donna M Neumann, James M Hill, Ashim K Mitra |
Journal | Journal 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 |
PMID | 16386088
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antiviral Agents
- Dipeptides
- Esters
- Ophthalmic Solutions
- Prodrugs
- Ganciclovir
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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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