Comparison of Ocular Pharmacokinetics of Dorzolamide and Brinzolamide in Pigmented Rabbit after Single and Multiple Topical Administrations

Abstract

Purpose: : The purpose of this study was to compare the ocular tissue distribution of dorzolamide and brinzolamide after single and multiple topical applications in the rabbit eye.

Methods: : Dutch-belted rabbits were treated with single or multiple topical administrations of 2% dorzolamide solution (30 µl) to one eye and 1 % brinzolamide suspension (30 µl) to the other eye. Rabbits were euthanized at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, and 24 hr post dosing. For multiple dosing, rabbits were dosed twice daily for 7, 14, and 21 days. In the multiple dosing studies, rabbits were euthanized at 1 hr after the last dose. In all cases, the eyes were enucleated, snap frozen and dissected in frozen state to isolate various tissues. After isolating tissues of the anterior segment, the remaining eye was dissected into anterior and posterior regions, in order to determine whether the drug distributes primarily to the anterior regions of the back of the eye tissues from an eye drop. Drug levels in tissue samples were measured using LC-MS/MS method. Cornea, aqueous humor, conjunctiva, sclera (anterior and posterior), retina (anterior and posterior), vitreous humor (anterior and posterior), and optic nerve were analyzed

Results: : Distribution to the aqueous humor, anterior and posterior sclera, anterior and posterior retina, anterior and posterior vitreous, and optic nerve was higher for dorzolamide than brinzolamide after single as well as multiple topical administrations at all time points. No significant differences were found in the delivery of these two drugs to the cornea and conjunctiva. Drug levels were significantly higher in anterior regions than posterior regions for sclera, retina, and vitreous for both drugs. After single topical dosing, AUC_0-t (µg.h/mL or g) of dorzolamide was 2-fold higher in aqueous humor, 7-fold higher in anterior sclera, 3.5-fold higher in posterior sclera, 1.5-fold higher in anterior retina, 1.9-fold higher in posterior retina, 4-fold higher in anterior vitreous, and 9-fold higher in optic nerve when compared to brinzolamide. No drug levels were detected in the posterior vitreous for brinzolamide at any time point after single dosing.

Conclusions: : Dorzolamide delivery to the aqueous humor, sclera, retina, vitreous, and optic nerve was greater than brinzolamide both after single and multiple topical administrations.

Keywords: carbonic anhydrase • anterior segment • retina