title: Distribution and metabolism of intravitreal cidofovir and cyclic HPMPC in rabbits.
abstract: OBJECTIVE
  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.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: G
authors.initials: G
authors.lastname: Lynch
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
authors.forename: M J
authors.initials: MJ
authors.lastname: Hitchcock
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D000077404:Cidofovir; D017726:Cytomegalovirus Retinitis / Q000150:complications / Q000188:drug therapy; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005123:Eye / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007267:Injections; D007668:Kidney / Q000378:metabolism; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C072572:cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; D003596:Cytosine; D000077404:Cidofovir