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pH and drug ionization affects ocular pressure lowering of topical carbonic anhydrase inhibitors
1University of Florida Health Science Center, Department of Pharmacology and Therapeutics, Gainesville 32610.
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.
Insights
Increasing drug ionization enhances the ocular hypotensive activity of topical carbonic anhydrase inhibitors. Ionized forms are better sequestered in the cornea, prolonging drug delivery and efficacy.
Area of Science:
- Ophthalmology
- Pharmacology
- Drug Delivery
Background:
- Topical carbonic anhydrase inhibitors are used to reduce intraocular pressure.
- Drug ionization is a critical factor influencing drug absorption and efficacy.
- Understanding ionization effects is key for optimizing glaucoma treatment.
Purpose of the Study:
- To investigate the relationship between drug ionization and ocular hypotensive effects.
- To evaluate how ionization impacts the activity of topical carbonic anhydrase inhibitors.
- To determine the role of ionization in corneal drug sequestration.
Main Methods:
- Tested three carbonic anhydrase inhibitors (MK-927, L-662,583, AHR-16329) at various concentrations and pH.
- Applied drugs topically to normotensive and hypertensive rabbit eyes.
- Measured intraocular pressure and analyzed drug levels in eye tissues.
Main Results:
- Higher drug ionization correlated with greater ocular hypotensive activity.
- Increased drug concentration was found in ocular tissues following application of ionized forms.
- Ionized carbonic anhydrase inhibitors demonstrated enhanced ocular penetration and retention.
Conclusions:
- Increasing ionization of topical carbonic anhydrase inhibitors boosts their ocular hypotensive efficacy.
- Ionized compounds are more readily sequestered in the cornea, acting as a drug depot.
- Corneal sequestration of ionized drugs facilitates prolonged therapeutic effects.