The accession of methazolamide in ionized and unionized form to cornea, sclera, aqueous humor and ciliary process was studied 10 minutes following separate application to either sclera or cornea of a 1 mM solution. Cornea and ciliary process concentrations were 27.3 and 14.5 microM for unionized application to cornea and 10.1 and 7.1 microM for ionized application. Bulk aqueous humor concentrations were much lower, 3.1 and 1.1 microM, and cannot account for drug found in ciliary process on this time scale. Scleral application of drug, by contrast, gave undetectable ciliary process concentrations. These results are presented as a model for drug disposition following single drop topical sulfonamide therapy. The scleral pathway for drug delivery to ciliary process was further tested by application to sclera of 300 microL of either a 1 mM ionized or unionized solution for 30 minutes or as a 2% (85.5 mM) ionized solution for 30 minutes. In these series, red cell carbonic anhydrase was presaturated at -24 hours with drug to remove a possible route for loss of drug from sclera, that of the systemic circulation and the high concentration of carbonic anhydrase in red cells. After either ionized or unionized application, approximately 1 microM was detected in ciliary process, but all drug was attributable to the blood content of the tissue and the drug bound to red cell carbonic anhydrase. After 2% dosing, 4 microM was detected in ciliary process after allowance for drug in red cells. This concentration is below that necessary for inhibition of ciliary process carbonic anhydrase, suggesting that especially with regard to topical sulfonamide therapy, the corneal route of drug delivery to ciliary process predominates greatly over the scleral route.