Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

Abstract

ABSTRACT:Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 l of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 l of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (C max , T max , and AUC 0-24 ) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC 0-24 ) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. C max was 2-to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4-to 3.2-, 2.4-to 2.7-, 2.2-to 4.5-, and 2.4-to 5.2-fold higher than those of brinzolamide. Upon multiple dosing, both drugs accumulated in all of the tissues except the conjunctiva, where the drug levels were lower than those observed with single dosing. No significant differences were found in the AUC values of these two drugs in the cornea and conjunctiva after single and multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in the sclera, retina, and vitreous for both drugs.

Effects of Dorzolamide on Retinal and Choroidal Blood Flow in the DBA/2J Mouse Model of Glaucoma

“… 21 In addition to its hypotensive effect, dorzolamide dilates isolated retinal arterioles 28 , 29 and so it may have a direct vasodilatory effect in vivo. However, although topical dorzolamide reaches the back of the eye, 30 , 31 its ability to increase blood flow in the retina, choroid and optic nerve has not been shown consistently. In rabbits, acute dorzolamide had no effect on choroidal perfusion, 32 but chronic dosing increased optic nerve head perfusion in one study 33 and had no effect in another.…”

Hydrophilic Prodrug Approach for Reduced Pigment Binding and Enhanced Transscleral Retinal Delivery of Celecoxib

“…Higher delivery of CSA to intraocular tissue is a result of its reduced pigment binding as well as an increase in concentration dependent flux. CSA has 300-fold higher solubility than celecoxib (Table 1); while soluble prodrug will be readily available for delivery, solubilization of the drug in suspension is rate limiting for celecoxib delivery 43 . A recent study of ours with drug suspensions showed that in vivo transscleral retinal delivery increases with an increase in corticosteroid solubility 44 .…”

Hydrogel Ring for Topical Drug Delivery to the Ocular Posterior Segment

“…Drugs administered to the ocular surface can reach the posterior segment relatively quickly (0.25-1 hour). 7,19 Therefore, drug concentrations in the tissue 1 hour after drug (Figure 3). The amount of drug in the conjunctiva, sclera, and retina/choroid of Ring 1treated and S/CL-treated eyes was significantly higher than that in OOS-treated and CL-treated eyes.…”