The ocular disposition of acycloguanosine analogs
Abstract
The prodrug approach was utilized in this research in an attempt to transiently alter the physicochemical properties of acyclovir and improve its corneal absorption. Six aliphatic 2$\sp\prime$-esters of acyclovir were synthesized and physicochemically characterized including propionyl, butyryl, isobutyryl, valeryl, hexanoyl and pivalyl esters. The compounds exhibited a 100 fold increase in lipophilicity, as measured by their n-octanol/buffer partition coefficients, upon esterification to the hexanoate ester (8.58 vs 0.06 for acyclovir) with only a 10 fold decrease in their solubilities (0.71 mM versus 11.18 mM). The ocular tissues homogenates metabolized the prodrugs to ACV indicating in vitro the ability of these tissues to regenerate the parent compound. Corneal membrane permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The corneal permeability of ACV (3.65 $\times\ 10\sp{-6}$ cm sec$\sp{-1})$ was increased 2.5 fold upon esterification to the hexanoate ester (8.45 $\times\ 10\sp{-6}$ cm sec$\sp{-1})$ and a similar increase in ocular availability was observed as the series was ascended to the valerate ester (8.85 ${\rm \mu M}$ versus 3.80 $\mu$M for ACV). The effectiveness of acyclovir butyrate and acyclovir valerate as treatments for primary herpetic keratitis was evaluated in the McKrae strain infected rabbit model. The compounds were as effective as ACV indicating that bioreversion of the prodrugs occurs in vivo. A novel ocular microdialysis-perfusion technique was developed that allowed for the continuous sampling of the vitreous humor for drug. The technique produced accurate and rapid vitreous drug concentration time profiles with a resolution of 20 minutes on the time axis. The vitreous elimination of ganciclovir and acyclovir was extremely rapid having vitreous half lives of 2.62 and 2.98 hours respectively and a transretinal mechanism of clearance was established for these compounds. Further, it was shown that the compounds do not exhibit saturation kinetics over the dosage ranges used in the clinical setting.
Degree
Ph.D.
Advisors
Mitra, Purdue University.
Subject Area
Pharmacology|Pharmaceuticals
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