Ocular disposition of novel lipophilic diester prodrugs of ganciclovir following intravitreal administration using microdialysis.

PURPOSE

The objective of the present study was to explore acyl diester prodrugs (acetate, propionate, and butyrate) of ganciclovir (GCV) to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time following intravitreal administration.

METHODS

Male New Zealand albino rabbits (2-2.5 kg) were used for these studies. Animals were kept under anesthesia throughout the course of an experiment using ketamine HCl and xylazine. A concentric microdialysis probe was implanted into the vitreous chamber with a 21-gauge needle and a linear microdialysis probe was inserted into the anterior chamber across the cornea using a 25-gauge needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 microl/min. GCV prodrugs (33.2 microg of diacetate, 35.9 microg dipropionate prodrugs, and 9.87 microg of dibutyrate prodrug) or GCV (50, 25, and 12.5 microg) were administered intravitreally and the microdialysis samples were collected every 20 minutes over a period of 10 hours.

RESULTS

Vitreal terminal elimination half-life of GCV was found to be similar with all three doses and ranged from 325 to 401 min. Elimination rate constant (lambda z) and vitreal clearance of diesters increased with the ester chain length. Vitreal elimination half-lives of GCV diacetate, dipropionate, and dibutyrate esters were found to be 112 +/- 37, 41.9 +/- 13.1, and 33.5 +/- 6.5 min, respectively. Mean residence time (MRT) of regenerated GCV (356 +/- 16 min, 341 +/- 11 min and 324 +/- 19 min from GCV diacetate, dipropionate and dibutyrate, respectively) increased by 2-fold following prodrug administration as compared to direct GCV administration (185 +/- 28 min).

CONCLUSIONS

GCV showed linear kinetics in the dose range studied. Acyl diester prodrugs of GCV generated therapeutic concentrations of GCV in vivo. Moreover, these studies have shown that MRT of GCV could be enhanced about 2-fold through prodrug modification.