Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations.
OBJECTIVE
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.
Majumdar
Soumyajit
S
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, 64110-2499, USA.
Nashed
Yasser E
YE
Patel
Kunal
K
Jain
Ritesh
R
Itahashi
Motoki
M
Neumann
Donna M
DM
Hill
James M
JM
Mitra
Ashim K
AK
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid; D003319:Corneal Stroma / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004355:Drug Stability; D019573:Epithelium, Corneal / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004952:Esters; D015774:Ganciclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D007322:Instillation, Drug; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000821:virology; D008297:Male; D015394:Molecular Structure; D009883:Ophthalmic Solutions; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D012995:Solubility
D000998:Antiviral Agents; D004151:Dipeptides; D004952:Esters; D009883:Ophthalmic Solutions; D011355:Prodrugs; D015774:Ganciclovir