Ocular pharmacokinetics of acyclovir amino acid ester prodrugs in the anterior chamber: evaluation of their utility in treating ocular HSV infections.
OBJECTIVE
To evaluate in vivo corneal absorption of the amino acid prodrugs of acyclovir (ACV) using a topical well model and microdialysis in rabbits.


METHODS
Stability of L-alanine-ACV (AACV), L-serine-ACV (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) prodrugs was evaluated in various ocular tissues. Dose-dependent toxicity of these prodrugs was also examined in rabbit primary corneal epithelial cell culture (rPCEC) using 96-well based cell proliferation assay. In vivo ocular bioavailability of these compounds was also evaluated with a combination of topical well infusion and aqueous humor microdialysis techniques.


RESULTS
Among the amino acid ester prodrugs, SACV was most stable in aqueous humor. Enzymatic degradation of EACV was the least compared to all other prodrugs. Cellular toxicity of all the prodrugs was significantly less compared to trifluorothymidine (TFT) at 5mM. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. All the prodrugs showed similar terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately two-fold increase in area under the curve (AUC) relative to ACV (p<0.05). Clast (concentration at the last time point) of SACV was observed to be 8+/-2.6microM in aqueous humor which is two and three times higher than VACV and ACV, respectively.


CONCLUSIONS
Amino acid ester prodrugs of ACV were absorbed through the cornea at varying rates (ka) thereby leading to varying extents (AUC). The amino acid ester prodrug, SACV owing to its enhanced stability, comparable AUC and high concentration at last time point (Clast) seems to be a promising candidate for the treatment of ocular HSV infections.
Katragadda
Suresh
S
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, United States.
Gunda
Sriram
S
Hariharan
Sudharshan
S
Mitra
Ashim K
AK
D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism; D019540:Area Under Curve; D001682:Biological Availability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D019573:Epithelium, Corneal / Q000378:metabolism; D016849:Keratitis, Herpetic / Q000188:drug therapy*; D008297:Male; D009883:Ophthalmic Solutions; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011817:Rabbits; D018675:Toxicity Tests
D000998:Antiviral Agents; D009883:Ophthalmic Solutions; D011355:Prodrugs; D000212:Acyclovir