The Study of Ocular Hypotensive Effect of 6-Hydroxyethoxy-2-benzothiazole Sulfonamide: A Topical Carbonic Anhydrase Inhibitor

Abstract

A newly synthesized topical carbonic anhydrase inhibitor, 6-hydroxyethoxy-2-benzothiazole sulfonamide (6-HS), was administered systemically and topically to alpha-chymotrypsin-induced glaucoma rabbits to evaluate its ocular hypotensive effect. A significant IOP lowering effect was observed after topical application of 50 pi of 3% 6-HS gel, but a dose of 50 p.1 of 3% 6-HS suspension failed to reduce IOP. The maximal magnitude of reduced IOP after topical gel instillation was 24.4%, very close to the result obtained following intravenous injection of 6 mg/Kg of 6-HS (23.3%). However, the blood levels of 6-HS after topical instillation with 3% 6-HS gel was much lower than that following 6 mg/Kg of 6-HS injected intravenously (less than 5%). Since a lower dose of 6-HS (1 mg/Kg) administered intravenously did not cause a significant drop in IOP, it is reasonable to deduct that the ocular hypotensive effect of 6-HS applied topically can then be attributed to the inhibition of intraocular carbonic anhydrase activity. It was also noted that a larger dose of intravenous administration of 6-HS (20 mg/Kg) had a more profound IOP and blood pressure reducing effect with moderate metabolic acidosis.

Biopharmaceutical Explanation for the Topical Activity of 6-Hydroxyethoxy-2-Benzothiazolesulfonamide in the Rabbit Eye

“…Although the metabolism of compounds 1-3 has not been established, from the work reported herein, the ability of compound 1 to lower IOP in rabbits (8,12), and monkeys (13) is quite possibly due to its enhanced accumulation at the active site as well as its ability to reach the active site equally well from both the corneal and conjunctival/scleral routes of administration. Conjunctival/scleral absorption permits direct access to the ciliary process without first entering aqueous humor which occurs following corneal penetration.…”

“…Surprisingly, the most active agents did not penetrate the cornea any more rapidly than methazolamide or ethoxzolamide, the topically inactive parent compounds (2,10,11). In a series of studies (8)(9)(10)(12)(13)(14) focusing on the IOP-lowering capability of 2-benzothiazolesulfonamide analogs, it was observed that only the poorly penetrating 6-amino and the 6-hydroxyethoxy substituted analogs were active in lowering IOP in high-pressure rabbit (8,12) and monkey eyes (13) when instilled topically.…”

“…The metabolite, 6-acetamido-2-benzothiazolesulfonamide, was synthesized and found to be active in inhibiting CAase in vitro but not active when instilled topically into either the high-pressure induced rabbit (8,12) or monkey eye (13). It was concluded that the metabolite, when formed at the active site by aryl Nacetyltransferase, was well retained but when dosed topically was not absorbed and/or distributed in sufficient concentrations to be active (14,15).…”

Studies of Topical Carbonic Anhydrase Inhibitors: Ocular Hypotensive Effect of Thiadiazole Derivatives

“…Recently, topical carbonic anhydrase inhibitors were developed for the treatment of glaucoma, such as 6-hydroxy-ethoxzolamide, aminozolamide and series of MK compounds (1)(2)(3)(4). During the course of such developments, a suitable candidate should not only consider the requirement of pharmacological activity, but also the influence of topical ocular absorption.…”