Intravitreal pharmacokinetics in rabbits of the foscarnet lipid prodrug: 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA).
OBJECTIVE
To evaluate the intraocular distribution and metabolism of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA), following intravitreal administration.


METHODS
Twenty rabbits received ODG-[14C]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal concentration. Two animals per group were sacrificed at different intervals post-injection. The drug levels in ocular tissues were determined with counting the radioactivity by Tracor Mark III Liquid Scintillation Counter. Four rabbits were used for analysis of the drug metabolism in vitreous by lipid extraction technique.


RESULTS
The drug level in vitreous was 526 microM at day one and 227 microM at the fifth week. The vitreous half life was approximately four to five weeks. The retinal level of the drug was 292 microM at day one, 75 microM at the fifth week and 32 microM at the tenth week, which was still more than ten times higher than the IC90 against HCMV. Lipid extraction analysis showed that, in vivo, both ODG-PFA and PFA were present in vitreous, but in in vitro incubations with vitreous, ODG-PFA conversion to PFA was negligible.


CONCLUSIONS
ODG-PFA possesses a long vitreous half life and sustained high drug level in retina. The vitreous did not metabolize drug but acted as a drug reservoir. Intravitreal liposomal ODG-PFA may be expected to be a long acting potent local therapy for CMV retinitis.
Cheng
L
L
Shiley Eye Center, UCSD, La Jolla, CA 92093, USA.
Hostetler
K Y
KY
Gardner
M F
MF
Avila
C P
CP
Bergeron-Lynn
G
G
Severson
G M
GM
Freeman
W R
WR
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D004337:Drug Carriers; D017245:Foscarnet / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D008081:Liposomes; D010742:Phospholipid Ethers / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011817:Rabbits; D012160:Retina / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism*
C119381:1-O-octadecyl-sn-glycerol-3-phosphonoformate; D000998:Antiviral Agents; D004337:Drug Carriers; D008081:Liposomes; D010742:Phospholipid Ethers; D011355:Prodrugs; D017245:Foscarnet