W F Brechue1, T H Maren. 1. University of Florida Health Science Center, Department of Pharmacology and Therapeutics, Gainesville 32610.
Abstract
PURPOSE: To evaluate the effect of drug ionization on the ocular hypotensive activity of topical carbonic anhydrase inhibitors. METHODS: Ocular normotensive New Zealand albino and ocular hypertensive Dutch Belted pigmented rabbits were used. Tonometric intraocular pressure levels were taken after topical application of 50 microliters of drug (at various concentrations and pH values) to one eye with the contralateral eye used as an untreated control. The drugs tested were MK-927, L-662,583, and AHR-16329. Eye tissues were analyzed for drug by our enzymatic methods. RESULTS: In all cases, the more ionized the applied drug the greater the ocular hypotensive activity. Tissue distribution studies showed that there was more drug found in the eye after the ionized form of a drug was applied than that found after application of the less ionized forms. CONCLUSIONS: Increasing the ionization of three ampholyte topical carbonic anhydrase inhibitors increases their ocular hypotensive activity. These data taken with ocular disposition data suggest that ionized compounds of this type are more readily sequestered in the cornea, which serves as a drug depot for prolonged drug delivery and activity.
PURPOSE: To evaluate the effect of drug ionization on the ocular hypotensive activity of topical carbonic anhydrase inhibitors. METHODS: Ocular normotensive New Zealand albino and ocular hypertensive Dutch Belted pigmented rabbits were used. Tonometric intraocular pressure levels were taken after topical application of 50 microliters of drug (at various concentrations and pH values) to one eye with the contralateral eye used as an untreated control. The drugs tested were MK-927, L-662,583, and AHR-16329. Eye tissues were analyzed for drug by our enzymatic methods. RESULTS: In all cases, the more ionized the applied drug the greater the ocular hypotensive activity. Tissue distribution studies showed that there was more drug found in the eye after the ionized form of a drug was applied than that found after application of the less ionized forms. CONCLUSIONS: Increasing the ionization of three ampholyte topical carbonic anhydrase inhibitors increases their ocular hypotensive activity. These data taken with ocular disposition data suggest that ionized compounds of this type are more readily sequestered in the cornea, which serves as a drug depot for prolonged drug delivery and activity.