Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations.
J Ocul Pharmacol Ther
; 21(6): 463-74, 2005 Dec.
Article
in En
| MEDLINE
| ID: mdl-16386088
ABSTRACT
PURPOSE:
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Prodrugs
/
Ganciclovir
/
Keratitis, Herpetic
/
Herpesvirus 1, Human
/
Dipeptides
Type of study:
Prognostic_studies
Language:
En
Journal:
J Ocul Pharmacol Ther
Journal subject:
FARMACOLOGIA
/
OFTALMOLOGIA
/
TERAPEUTICA
Year:
2005
Document type:
Article
Affiliation country:
United States