1 L‐662,583 was a potent inhibitor in vitro of purified, human erythrocyte carbonic anhydrase II, possessing an IC50 of 0.7 nm. The IC50 values for MK‐927, acetazolamide and methazolamide were 13.0 nm, 10.8 nm and 21.2 nm, respectively. 2 A 1 h pretreatment with one 50 μl drop of a 0.1% solution of L‐662,583 blocked carbonic anhydrase activity in a homogenate of the iris + ciliary body of albino rabbits by 63%. Similar treatment with 0.1% suspensions of acetazolamide and methazolamide elicited inhibitions of 30% and 20%, respectively. This ex vivo model indirectly assesses the ability of an agent to enter the rabbit eye. 3 Concentrations of L‐662,583 in the cornea, aqueous humour and iris + ciliary body of albino rabbits were determined by h.p.l.c. at predetermined times after the instillation (one drop of 50 μl) of a 2% solution of L‐662,583. Peak levels for cornea (47.4 μg g−1), aqueous humour (4.51 μg ml−1) and iris + ciliary body (9.61 μg g−1) occurred at 0.5, 2 and 1 h after instillation, respectively. 4 The experimentally elevated intraocular pressure of the right eye of rabbits, induced by prior intraocular injection of α‐chymotrypsin, was maximally decreased by 4.5 mmHg, 6.2 mmHg and 9.8 mmHg after the instillation (one drop of 50 μl) of 0.01%, 0.1% and 0.5% solutions of L‐662,583, respectively. All three concentrations lowered intraocular pressure at all time points from 1 h up to and including 5 h, the last recorded time point. The unilateral instillation of L‐662,583 (0.5%) into the contralateral, left eye failed to lower the elevated intraocular pressure of the untreated, right eye. This finding indicates that the site of action of topically applied L‐662,583 in this paradigm is local. The ocular normotensive, albino rabbit was much less susceptible than the ocular hypertensive rabbit to the intraocular pressure lowering effect of topically applied L‐662,583, with a 2% solution maximally decreasing intraocular pressure by 2.3 mmHg. 5 Unilateral ocular hypertension was elicited in the right eye of sedated, cynomolgus monkeys by argon laser‐induced photocoagulation of the trabecular meshwork. The instillation (one drop of 50 μl) of L‐662, 583 (2%) significantly lowered the elevated intraocular pressure of the right eye at all time points from 1 h up to and including 5 h. The maximum decline was 8.3 mmHg at 3 h and this represented a reduction of 23% from the corresponding baseline value of 36.8 mmHg. The intraocular pressure of the hypertensive, right eye was maximally decreased by 4.1 mmHg and 4.8 mmHg after the instillation of 0.5% and 1% solutions of L‐662,583, respectively. Like the rabbit, the normotensive eye of cynomolgus monkeys was more resistant than the hypertensive eye to the ocular hypotensive action of L‐662, 583, as indicated by the inability of 0.5% and 1% solutions of the agent to lower intraocular pressure. L‐662,583 (2%) maximally reduced the intraocular pressure of normotensive monkey eyes by 2.4 mmHg at 2 h. 6 L‐662,583 is structurally different from MK‐927, a carbonic anhydrase inhibitor that lowers the intraocular pressure of glaucoma patients following the instillation of a 2% solution. These preclinical observations indicate that L‐662,583, like MK‐927, is a water‐soluble carbonic anhydrase inhibitor which, on topical administration, lowers intraocular pressure by virtue of an action confined to within the eye.
M. F. Sugrue, P. Gautheron, P. Mallorga
British Journal of Pharmacology