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Relations among IOP reduction, ocular disposition and pharmacology of the carbonic anhydrase inhibitor ethoxzolamide

1992; Elsevier BV; Volume: 55; Issue: 1 Linguagem: Inglês

10.1016/0014-4835(92)90094-9

1096-0007

Thomas H. Maren, William F. Brechue, Amir Bar-Ilan,

Retinal Development and Disorders

We have measured sequentially the concentrations of ethoxzolamide (6-ethoxybenzothiazole-2-sulfonamide) in ocular tissues following its intravenous or topical administration to normal albino rabbits. This was done in parallel with determinations of intraocular pressure (IOP) measured by tonometer or direct manometry. Ethoxzolamide was used because of its very high activity against carbonic anhydrase and experience showing that there is little or no other receptor in tissues. During the course of these experiments it was discovered that the lipid-soluble ethoxzolamide is converted in vivo to a water-soluble metabolite, while retaining high activity against the enzyme. Presumably this is the 6-O-glucuronide adduct. At the minimal dose for maximal effect (4 mg kg−1 i.v. at 45 min) the IOP lowering was 4·2 mmHg, the concentration in anterior uvea was 2·5 μmol kg−1, and the fractional inhibition of the enzyme (i) was 0·9995. The effect declined rapidly, attributable to the very short half-life of drug in plasma, leading to depletion of free drug in the anterior uvea and other tissues. Following topical administration i was measured as a function of drug and enzyme in ciliary process. IOP lowering at 1 hr was −1·9 mmHg and i = 0·9993. By 4 hr i = 0·9980 and the pharmacological effect disappeared. At 8 hr the concentration of ethoxzolamide in the ciliary process is 0·4 μmol kg−1, essentially that of enzyme, with no free drug present: drug is now a marker for enzyme. Ethoxzolamide also labels the red cell carbonic anhydrases in the rabbit as well as other species including man. There appears to be no ethoxzolamide receptor other than carbonic anhydrase. Contrast is provided to the sulfonamide carbonic anhydrase inhibitors now being developed for topical use (cf. MK-927) which have secondary functional groups that may bind to other tissue receptors.