Distribution and metabolism of intravitreal cidofovir and cyclic HPMPC in rabbits

• Published in: Current eye research Vol. 15; no. 5; p. 569
• Main Authors: Cundy, K C, Lynch, G, Shaw, J P, Hitchcock, M J, Lee, W A
• Format: Journal Article
• Language: English
• Published: England 01.05.1996
• Subjects: AIDS-Related Opportunistic Infections - drug therapy; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - metabolism; Antiviral Agents - pharmacokinetics; Cidofovir; Cytomegalovirus Retinitis - complications; Cytomegalovirus Retinitis - drug therapy; Cytosine - administration & dosage; Cytosine - analogs & derivatives; Cytosine - metabolism; Cytosine - pharmacokinetics; Eye - metabolism; Half-Life; Humans; Injections; Kidney - metabolism; Male; Organophosphonates; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - metabolism; Organophosphorus Compounds - pharmacokinetics; Rabbits; Retina - metabolism; Tissue Distribution; Vitreous Body - metabolism
• ISSN: 0271-3683
• DOI: 10.3109/02713689609000768

This study was designed to evaluate the intraocular distribution and metabolism of the antiviral nucleotide analogs cidofovir and cyclic 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits following intravitreal administration. Male rabbits received either 14C-cidofovir or 14C-cyclic HPMPC by intravitreal injection into both eyes (50 micrograms/eye, 11 microCi/eye). Two animals per group were sacrificed at 24, 48, 72 or 240 h post-dose. Ocular tissues, kidney and liver were oxidized to determine total radioactivity and metabolites were determined by HPLC. At 24 h post-dose, total radioactivity was 9.96 and 5.18 micrograms-equiv/g for cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54 micrograms-equiv/g, respectively, in retina. Although the initial vitreal clearance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar for both drugs. By 240 h post-dose, radioactivity in all ocular tissues was approximately ten-fold higher for cidofovir. Radioactivity in vitreous at 240 h after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine. The long retinal half-life observed presumably reflects formation of phosphorylated cidofovir within retinal cells. Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than cyclic HPMPC: Therefore, intravitreal cidofovir may be expected to suppress progression of retinitis for a longer period than an equivalent intravitreal dose of cyclic HPMPC: The intravitreal half-life of cidofovir was 20-fold longer than that of ganciclovir in the same animal model.