title: Intraocular pharmacokinetics of a crystalline lipid prodrug, octadecyloxyethyl-cyclic-cidofovir, for cytomegalovirus retinitis.
abstract: OBJECTIVE
  To evaluate the intraocular pharmacokinetics of octadecyloxyethyl-cyclic-cidofovir (ODE-cCDV) after intravitreal injection into rabbit eyes.
  
  
  METHODS
  Twenty-seven New Zealand red rabbits (27 eyes) received intravitreal injections of (14)C-labeled ODE-cCDV (100 μg drug suspended in 5% dextrose), and ocular tissues were collected from 3 rabbits at each predetermined time point (1 h, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks, and 9 weeks) after the injection. The eye globes were enucleated, and the vitreous, retina, and choroids were separated and harvested into pre-weighed scintillation vials. Levels of ODE-cCDV were measured by counting in a liquid scintillation counter, and pharmacokinetic (PK) parameters were determined. In addition, 3 eyes of 3 animals were used for autoradiography study at day 1, week 3, and week 6.
  
  
  RESULTS
  ODE-cCDV in vitreous as a whole followed a 2-phase first-order elimination, whereas ODE-cCDV in retina and choroid manifested a nearly steady state during the first 3 weeks and then followed a first-order elimination with the apparent elimination half-life of 10.1 and 7.2 days. For vitreous, apparent elimination half-life was 25 days. However, the drug mean residence time was much longer in retina (17.6 days) and choroid (19.6 days) than that in the vitreous (11.6 days). The drug exposure to the retina [area under the curve (AUC) = 1120837.1 ng · day/mL] was greater than the exposure to the vitreous (AUC = 958645.8 ng · day/mL) and the choroid (AUC = 415407.47).
  
  
  CONCLUSIONS
  A crystalline lipid prodrug, ODE-cCDV, has longer vitreous half-life than that in other ocular tissues due to its solid drug depot formation in vitreous. Over time, dissolved free ODE-cCDV from drug depot feeds and accumulates in the retina.
authors.affiliation: Department of Ophthalmology, Jacobs Retina Center at Shiley Eye Center, University of California-San Diego, 9415 Campus Point Drive, La Jolla, CA 92093-0946, USA. cheng@eyecenter.ucsd.edu
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Ajay
authors.initials: A
authors.lastname: Tammewar
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Carl
authors.initials: C
authors.lastname: Hoh
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D001345:Autoradiography; D000077404:Cidofovir; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D005123:Eye / Q000378:metabolism*; D058449:Intravitreal Injections; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000493:pharmacokinetics*; D011817:Rabbits
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C560440:octadecyloxyethyl-cyclic-cidofovir; D003596:Cytosine; D000077404:Cidofovir