PT  - JOURNAL ARTICLE
AU  - Maren, Thomas H.
TI  - THE RELATION BETWEEN ENZYME INHIBITION AND PHYSIOLOGICAL RESPONSE IN THE CARBONIC ANHYDRASE SYSTEM
DP  - 1963 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 140--153
VI  - 139
IP  - 2
4099  - http://jpet.aspetjournals.org/content/139/2/140.short
4100  - http://jpet.aspetjournals.org/content/139/2/140.full
SO  - J Pharmacol Exp Ther1963 Feb 01; 139
AB  - Five carbonic anhydrase inhibitors of varying structural types, physical properties, and potency were studied with respect to their concentration in the kidney, and their renal effect. Although they gained access to the renal cortex by the differing routes of diffusion and active secretion, renal HCO3- excretion was a function of their KI and total concentration (I0) in the tissue. The dose-response curve corresponded to inhibition ranging from about 99% (minimal or no effect) to 99.95% (maximal effect). This agrees with other studies which show carbonic anhydrase to be present in kidney in 1000-fold excess of maximum physiological needs. Review of doses used and concentrations of drug found for other organs (red cell, pancreas, stomach, ciliary process, salt gland) shows that it is generally the case that over 99% of enzyme must be inhibited to show physiological effects. Actual enzyme concentration at these sites insofar as they have been studied are correspondingly in excess of those needed for physiological secretion rates. Correlation of inhibition kinetics with the physiological response in the ciliary process and red cells suggests that in these tissues, unlike the kidney, there are barriers which exclude anionic drugs from the enzyme site. For the largely unionized drugs, however, the quantitative degree of inhibition is a function of (I0) and (E0) in all organs studied. It is demonstrated that for very potent inhibitors of carbonic anhydrase (KI ∼ 10-8 M) the dose-response curve will be strikingly influenced by the concentration of enzyme in tissues. For weak inhibitors, as in classical Michaelis-Menten kinetics, enzyme concentration will not influence these relations. The overall data suggest that carbonic anhydrase is the dominant receptor in tissues for monosulfonamides of the general type aryl-SO2NH2.