Drug Pharmacokinetics in Rat Eye Tissues Following Topical Administration: Brimonidine

Abstract

Abstract: : Purpose: The rabbit is the species of choice in conducting preclinical ocular pharmacokinetic studies. Pharmacokinetic studies in the rabbit usually involve serial sacrifice of subjects with excision of ocular tissues, although more sophisticated techniques such as micro-dialysis have been employed. The rat is a primary preclinical species in models designed to study retinal degenerative diseases such as AMD and RD. However, the rat is not widely reported as a preclinical species for pharmacokinetic studies. This research examines the pharmacokinetics of a topically applied drug in the rat with excision of anterior and posterior tissues. We chose brimonidine as an initial test substance since this compound has been reported to distribute to the retina of rabbits and monkeys following topical ocular administration. Methods: Rats were dosed with 0.005 mL of a 0.15% [3-H]brimonidine tartrate solution buffered to pH 7.3. Animals were sacrificed at 10, 20, 30 and 60 minutes (n=1 per time point). Eye globes, retina, sclera, vitreous, lens and cornea were excised and combusted for radioanalysis. Results: Cmax was 6.28, 0.13, 0.98, 0.61, 1.39 µg*equivalents/g in the cornea, lens, vitreous, retina and sclera, respectively. Not surprisingly, concentrations of drug were highest in the cornea. In addition, the slower distribution of drug into the lens is not unexpected. The approximate amount of drug in retina was similar to what has been reported for Cmax in retina of rabbits following topical administration. Conclusions: The drug concentrations determined in ocular tissues showed tissue and time dependence and was not in disagreement with what would be expected based upon the literature. The excision of retina, sclera, vitreous, lens and cornea under a dissecting microscope from the rat was time consuming and it was concluded that excision of the retina alone would be sufficient for most studies examining the pharmacokinetics of drugs distributing to the retina following local ocular administration.

Keywords: drug toxicity/drug effects