Pharmacokinetics of intravitreal 5-fluorouracil prodrugs in silicone oil: experimental studies in pigs.
OBJECTIVE
To examine the in vivo pharmacokinetics of intravitreal 5-Fluorouracil (5-FU) following tamponade with 5-FU prodrug silicone oil formulations.


METHODS
Two different alkoxycarbonyl 5-FU prodrugs denoted C12 and C18 were synthesized and formulated as silicone oil suspensions. A total of 26 pigs underwent conventional three-port lens-sparing pars plana vitrectomy. Approximately 1.6 ml of the prodrug-silicone oil formulation was placed in the vitreous cavity. Operated eyes were enucleated between 20 min and 168 hours postoperatively, and analysed for their content of free 5-FU by high performance liquid chromatography.


RESULTS
With the C12 prodrug silicone oil formulation, the concentration of free 5-FU in the vitreous water phase 1 hour after surgery was 3.30 +/- 1.62 microg/ml. After 4 hours this concentration had declined to 1 microg/ml. With the C18 prodrug, the concentration of free vitreal 5-FU never reached 1 microg/ml during the 7 days these experiments lasted. A mathematical model is presented that can explain the measured data if the clearance of 5-FU from the vitreous water phase follows first order kinetics with a half-life of 20 min.


CONCLUSIONS
These experiments, and the model analysis, suggest that the elimination half-life of 5-FU in the vitreous cavity of a vitrectomized, silicone oil-filled eye is very fast. The model analysis indicates that an alkoxycarbonyl 5-FU prodrug with a specific release rate constant of 10.7 microg/square root h cm(2) can maintain an intravitreal 5-FU concentration above 1 microg/ml for 5 days in the porcine eye.
Schmidt Laugesen
Caroline
C
Eye Department, National University Hospital, Rigshospitalet, Copenhagen, Denmark.
Steffansen
Bente
B
Scherfig
Erik
E
la Cour
Morten
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001834:Body Water / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006207:Half-Life; D008962:Models, Theoretical; D011355:Prodrugs / Q000493:pharmacokinetics*; D012827:Silicone Oils; D013552:Swine; D014821:Vitrectomy; D014822:Vitreous Body / Q000378:metabolism* / Q000601:surgery
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D012827:Silicone Oils; D005472:Fluorouracil