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Direct measurements of the rate constants of sulfonamides with carbonic anhydrase

TH Maren

University of Florida Health Science Center, Department of Pharmacology and Therapeutics, Gainesville 32610-0267.

Kinetic values for 14 sulfonamides and carbonic anhydrase (equivalent of isozyme II) were determined directly by measurement of association rate constants (kon) and equilibrium constants (KI), yielding dissociation rate constants, koff. Values for kon (in liter/mol sec-1) ranged from 0.003 to 31 x 10(6), whereas KI ranged from 0.7 to 17,000 x 10(-9) M. The koff range was very small, 0.01-0.05 sec-1. Thus, the activity, which is usually thought of as reflecting KI, is entirely a function of the association rate. This is not the common situation in enzyme-inhibitor reactions. The koff range is faster by several orders of magnitude than drug decay from plasma, so equilibrium is always achieved at the enzyme site in vivo, after parenteral administration of acetazolamide, methazolamide, or ethoxzolamide. For topical administration, as for MK-927 to reduce intraocular flow and pressure, the quantitative relation between free drug in tissue and that bound to enzyme in ciliary process is not so clear. Thus, koff might be an independent factor in pharmacological activity. The reaction of anions with carbonic anhydrase is entirely different, in that variations in KI are chiefly determined by koff.

Volume 41, Issue 2, pp. 419-426, 02/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1992 by the American Society for Pharmacology and Experimental Therapeutics