THE PRECLINICAL PHARMACOLOGY OF DORZOLAMIDE HYDROCHLORIDE, A TOPICAL CARBONIC-ANHYDRASE INHIBITOR

Dorzolamide hydrochloride ylthieno[2,3-b]thiopyran-2-sulfonamide-7,7-d ioxide HCl; MK-507; L-671,152) is a water-soluble, potent inhibitor of human carbonic anhydrase isoenzymes II and IV in vitro, the respectiv e IC50 values being 0.18 nM and 6.9 nM. In contrast, it was found to b e a much weaker inhibitor of human carbonic anhydrase isoenzyme I (IC5 0 value of 600 nM). The topical administration of one 50 mu l drop of 0.5%, 1% and 2% solutions of dorzolamide maximally lowered the intraoc ular pressure (IOP) of glaucomatous monkeys by 22%, 30% and 37%, respe ctively. Good ocular hypotensive activity was also observed in ocular normotensive and hypertensive rabbits. Its site of action was within t he eye, and the reductions in IOP in both species was achieved via dec reased aqueous humor inflow. The duration of action of 2% dorzolamide was shorter than that of 0.5% timolol in glaucomatous monkeys. The IOP lowering activity of timolol in this paradigm was enhanced by the con comitant instillation of dorzolamide. Both acutely and repeatedly admi nistered 2% dorzolamide did not decrease regional ocular blood flow in the rabbit, and the topical instillation of the drug had no adverse e ffects on the eye of rabbits, dogs and monkeys. Dorzolamide has been a pproved in a number of countries for use in patients with ocular hyper tension or open-angle glaucoma.