Ethoxzolamide is a carbonic anhydrase inhibitor with Ki of 1 nM.
Ethoxzolamide (ETZ) treatment causes >90% inhibition of reporter GFP fluorescence in infected macrophages. Moreover, in a 9-day macrophage survival assay, Ethoxzolamide (ETZ) treatment significantly inhibits the ability of M. tuberculosis to grow intracellularly[2].
It is discovered that the lipid-soluble ethoxzolamide is converted in vivo to a water-soluble metabolite, while retaining high activity againstt the enzyme. At the minimal dose for maximal effect (4 mg/kg i.v. at 45 min) the IOP lowering is 4.2 mmHg, the concentration in anterior uvea is 2.5 pmol/kg, and the fractional inhibition of the enzyme (i) is 0.9995. The effect declines rapidly, attributable to the very short half-life of drug in plasma, leading to depletion of free drug in the anterior uvea and other tissues[1]. Ethoxzolamide (ETZ) strongly downregulates GFP reporter fluorescence in mouse lungs, with 3-fold inhibition of GFP signal compare to that in the mock-treating control. There is a significant reduction of bacterial survival in the lungs of ETZ-treating mice compare to the mock-treating control[2].
[1]. Maren TH, et al. Relations among IOP reduction, ocular disposition and pharmacology of the carbonic anhydrase inhibitor ethoxzolamide. Exp Eye Res. 1992 Jul;55(1):73-9. [2]. Benjamin K. Johnson, et al. The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits theMycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence. Antimicrob Agents Chemother. 2015 Aug; 59(8): 4436-4445. [3]. Song Gao, et al. Development and validation of an UPLC-MS/MS method for the quantification of ethoxzolamide in plasma and bioequivalent buffers: Applications to absorption, brain distribution, and pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Apr 1; 0: 54-59.