Pharmacokinetics of intravitreal 5‐fluorouracil prodrugs in silicone oil: experimental studies in pigs

Abstract

To examine the in vivo pharmacokinetics of intravitreal 5-Fluorouracil (5-FU) following tamponade with 5-FU prodrug silicone oil formulations. 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. 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. 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.