PT  - JOURNAL ARTICLE
AU  - Rajendra S Kadam
AU  - Gajanan Jadhav
AU  - Miller Ogidigben
AU  - Uday B Kompella
TI  - Ocular Pharmacokinetics of Dorzolamide and Brinzolamide Following Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow
AID  - 10.1124/dmd.111.040055
DP  - 2011 Jun 14
TA  - Drug Metabolism and Disposition
PG  - dmd.111.040055
4099  - http://dmd.aspetjournals.org/content/early/2011/06/14/dmd.111.040055.short
4100  - http://dmd.aspetjournals.org/content/early/2011/06/14/dmd.111.040055.full
AB  - Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distribution of commercially available carbonic anhydrase inhibitors to the optic nerve is 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 μl of Trusopt® (dorzolamide hydrochloride ophthalmic solution, 2 %) to one eye and 30 μl of Azopt® (brinzolamide ophthalmic suspension, 1 %) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 hrs and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice a day with 8 hr interval between 2 doses and groups of rabbits were euthanized at 7, 14, and 21 days at 1 hr after the last dose and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using LC-MS/MS. Pharmacokinetic parameters (Cmax, Tmax, and AUC0-24) were estimated by noncompartmental analysis. After single dose, dorzolamide delivery (AUC0-24) 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 brinzolamide. Cmax was 2- to 5- fold higher for dorzolamide than brinzolamide in all ocular tissue. After multiple dosing, dorzolamide levels in aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Upon multiple dosing, both drugs accumulated in all tissues except conjunctiva, where the drug levels were lower than those observed with single dosing. Dorzolamide levels in aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4-3.2-, 2.4-2.7-, 2.2-4.5-, and 2.4-5.2-fold higher than brinzolamide. No significant differences were found in the AUC of these two drugs in the cornea and conjunctiva after single as well as multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in sclera, retina, and vitreous for both drugs.