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.