title: The transcorneal permeability of sulfonamide carbonic anhydrase inhibitors and their effect on aqueous humor secretion.
abstract: Eleven sulfonamide carbonic anhydrase inhibitors of varied chemical and physical types were studied with respect to transcorneal permeability and reduction of intraocular flow and pressure. Using the isolated rabbit cornea, a constant drug concentration on the epithelial side and 6 ml solution in the endothelial chamber, first order rate constants (kin) ranged from 0 . 1-40 X 10(-3)/hr, roughly proportional to their lipid solubility. Drugs on the high side of this range were generally water insoluble and had pKa's too high to yield sodium salts at useful pH; therefore, the actual amount of drug delivered was small. We sought compounds which combined low pKa, good lipid solubility, and high activity against the enzyme. Trifluormethazolamide (TFM) has a pKa of 6 . 6, ether partition coefficient of 6, and a K1 of 2 X 10(-8)M. kin is 3 X 10(-3)/hr. TFM and five other compounds were also studied in vivo for their ability to penetrate the eye into the anterior and posterior chambers. These rate constants were roughly proportional to those measured in vitro; however, significant differences in accession to the two chambers were observed, as a function of varying physico-chemical properties of the drugs. A 3% solution of TFM (100 mM) applied to the rabbit eye for 25 min generated 0 . 7 mM in the anterior chamber and 0 . 07 mM in the posterior. Tissue distribution of TFM (and its metabolite) showed a relatively high concentration in the ciliary body 6 hr after dose. Intraocular pressure was reduced by 4 mmHg. With 10 min exposure this concentration of TFM reduced pressure by about 1 . 7 mmHg. Although the use of this drug is limited by its chemical instability and the length of exposure needed, the principle of treating glaucoma by the topical use of carbonic anhydrase inhibitors appears feasible.
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002415:Cats; D002463:Cell Membrane Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D005123:Eye / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D011817:Rabbits; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides