DISTRIBUTION AND METABOLISM OF INTRAVITREAL CIDOFOVIR AND CYCLIC HPMPC IN RABBITS

Purpose. This study was designed to evaluate the intraocular distribut ion and metabolism of the antiviral nucleotide analogs cidofovir and c yclic 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits following intravitreal administration. Meth ods. Male rabbits received either C-14-cidofovir or C-14-cyclic HPMPC by intravitreal injection into both eyes (50 mu g/eye, 11 mu Ci/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 ra dioactivity and metabolites were determined by HPLC. Results. At 24 h post-dose, total radioactivity was 9.96 and 5.18 mu g-equiv/g for cido fovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54 mu g-equiv/g, respectively, in retina. Although the initial vitreal clea rance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) we re similar for both drugs. By 240 h post-dose, radioactivity in all oc ular tissues was approximately ten-fold higher for cidofovir. Radioact ivity in vitreous at 240 h after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine. Conclu sions. The long retinal half-life observed presumably reflects formati on of phosphorylated cidofovir within retinal cells. Cidofovir achieve d 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 intrav itreal dose of cyclic HPMPC. The intravitreal half-life of cidofovir w as 20-fold longer than that of ganciclovir in the same animal model.