Ocular penetration of acyclovir and its peptide prodrugs valacyclovir and val-valacyclovir following systemic administration in rabbits: An evaluation using ocular microdialysis and LC-MS.
OBJECTIVE
To investigate the ocular penetration of acyclovir and its prodrugs following systemic administration and to elucidate the mechanism of penetration.


METHODS
Hydrophilic peptide prodrugs of acyclovir were infused intravenously in New Zealand albino rabbits over 45 min at a dose equivalent to 30 mmoles/kg acyclovir. Aqueous and vitreous humor samples were obtained utilizing ocular microdialysis and blood samples were obtained from the mid ear vein using a cannula.


RESULTS
The plasma bioavailability for acyclovir, valacyclovir and val-valacyclovir were similar with area under curve values being 896.24 (+/-143.58), 776.54 (+/-197.52), 824.69 (+/-217.43) min x micromoles/L respectively. Anterior segment area under curve values were 53.70 (+/-35.58), 139.85 (+/-9.43) and 291.05 (+/-88.13) min x micromoles/L respectively while the mean residence time values were 46.47 (+/-24.94), 76.30 (+/-7.24) and 188.39 (+/-80.73) min respectively. Vitreous levels of the prodrugs were not measurable.


CONCLUSIONS
The valine and valine-valine ester prodrugs of ACV penetrated the anterior segment of the eye much better than acyclovir alone, probably via a carrier mediated transport mechanism.
Dias
Clapton
C
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110-2499, USA.
Nashed
Yasser
Y
Atluri
Harisha
H
Mitra
Ashim
A
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004151:Dipeptides / Q000493:pharmacokinetics; D005069:Evaluation Studies as Topic; D005123:Eye / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis / Q000379:methods; D023421:Models, Animal; D009799:Ocular Physiological Phenomena / Q000187:drug effects; D011355:Prodrugs / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism
D000998:Antiviral Agents; D004151:Dipeptides; D011355:Prodrugs; C473736:val-valacyclovir; D014316:Tritium; C004194:glycylsarcosine; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir