ABSTRACT
Benzolamide, an orphan drug belonging to the pharmacological class of sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) is widely used in many physiological and pharmacological studies, together with the clinically employed classical drugs, acetazolamide, methazolamide, ethoxzolamide or dichlorophenamide, it being frequently stated that benzolamide is a membrane-impermeant inhibitor. We prove here that this is false: in fact benzolamide is rather similar to acetazolamide from the point of view of penetrability through blood red cell membranes. Unlike these neutral drugs, the cationic, positively-charged CAIs incorporating either tetraalkyl ammonium or pyridinium moieties, due to their salt-like character are indeed membrane-impermeant, being the only type of low molecular weight compound possessing such properties. Selective inhibition of membrane-associated CA isozymes is relevant indeed in many physiological studies and also pharmacologically, since the tumor-associated isozymes (CA IX and XII) are both membrane-bound.
Subject(s)
Benzolamide/metabolism , Benzolamide/pharmacology , Carbonic Anhydrase Inhibitors/metabolism , Cell Membrane Permeability , Benzolamide/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Erythrocyte Membrane/chemistry , Erythrocyte Membrane/drug effects , Erythrocyte Membrane/enzymology , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
In the past five years we have studied the penetration of locally applied sulfonamides into the eye, with a view toward developing new topical carbonic anhydrase inhibitors for the treatment of glaucoma. The drugs varied by 400 fold in their permeability to the anterior chamber and 20,000 fold in permeability to the posterior chamber. We report now on two particular findings related to drug structure: 1) Transcorneal permeability of the ionic or dissociated form of the drug is relatively high -- some 1/4 that of the undissociated form. 2) Depending on the structure, certain compounds are sequestered in the cornea (presumably the stroma) and form a release system into the anterior aqueous.