Part I. Vitreous disposition of alcohols as a function of lipophilicity. Part II.Transporter mediated delivery of acycloguanosine antivirals to retina

Part I. Anatomic and physiological barriers limit drug delivery to posterior segment via topical or systemic administration. Intravitreal administration has proven to be safe and effective means of treating retinal diseases. Physicochemical properties (lipophilicity and molecular size) dictate the elimination characteristics from vitreous body. This information is critical for effective design of intravitreal drug delivery systems. Therefore, vitreous disposition of homologous series of alcohols ranging from hydrophilic methanol to lipophilic 1-heptanol was delineated by microdialysis. The vitreous elimination half-lives of alcohols ranged from 52 +/- 6 min for methanol to 153 +/- 22 min for 1-heptanol. The vitreous elimination rates of alcohols progressively decreased with ascending chain length and lipophilicity. Part II. Ganciclovir is the drug of choice for treatment of cytomegalovirus retinitis. Ganciclovir distribution to retina from systemic circulation is restricted by blood retinal barrier. Limited permeability across blood retinal barrier and high systemic toxicity of intravenous therapy has led to intravitreal administration of ganciclovir. Nonetheless, after intravitreal injection, uptake of ganciclovir into retinal neural cells is limited due to its hydrophilic nature. Targeting drug molecules to transporters expressed on the blood retinal barrier and retina through prodrug derivatization presents a promising approach to enhance ganciclovir retinal concentrations. Expression of peptide transporter on blood ocular barriers and the presence of large neutral amino acid transporter (LAT) on retina have been investigated. Functional evidence for the presence of an oligopeptide transporter on blood-ocular barriers was obtained by studying the ocular uptake of glycylsarcosine following systemic administration. Furthermore, functional activity and molecular expression of LAT1 isomer on rabbit retina has been demonstrated. gamma-Glutamate and phenylalanine amino acid monoester prodrugs of ganciclovir and acyclovir targeting LAT1 on retina were studied. Inhibition of L-phenylalanine retinal uptake in the presence of prodrugs following intravitreal administration indicated that these prodrugs are substrates for LAT1 present on retina. Vitreal elimination half-lives of gamma-glutamate esters were higher relative to phenylalanine esters. Prodrugs generated sustained levels of acycloguanosines following intravitreal administration. Amino acid transporter targeted prodrug derivatization of acycloguanosines can be utilized to enhance the retinal delivery and to augment the intravitreal pharmacokinetic profile of ganciclovir.