Distribution and metabolism of intravitreal cidofovir and cyclic HPMPC in rabbits.
| Autor: | Cundy KC; Gilead Sciences, Inc., Foster City, CA 94404, USA., Lynch G, Shaw JP, Hitchcock MJ, Lee WA |
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| Jazyk: | angličtina |
| Zdroj: | Current eye research [Curr Eye Res] 1996 May; Vol. 15 (5), pp. 569-76. |
| DOI: | 10.3109/02713689609000768 |
| Abstrakt: | Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. |
| Databáze: | MEDLINE |
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