Studies on a Metal-helating Action of Furosemide

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Our previous report revealed a metal-chelating ability of thiazide diuretics upon a polarographic analysis, but failed to discover a metal-chelating ability of furose- mide, a potent, thiazide related diuretic. Then, the question was left whether a metal-chelating ability is an essential physico-chemical property of thiazide and its related diuretics. This study aimed to clarify a metal-chelating ability of furosemide by titration in dioxane-water solution and to calculate the stability constant (log Kc) by Bjerrum's method modified by Nozawa and Hatano. Experiments were carried out, as follows: 1) Titration curve of 20ml of 10-2 M/l of furosemide solution (solvent composed of 4 dioxane and 1 aq. dist.) was recorded by using 0.1-NaOH after an addition of 3 ml of 0. 1 N-HCl. 2) Titration curves of the mixture of furosemide, HCl and CuCl2 (solvent and concentration of furosemide and HCl were same as above described and concentration ratio of furosemide/Cu was 4, 3, 2, 1, respectively.) were also recorded. 3) Titration curves of the mixture of furosemide, HCl and MgCl2 or ZnCl2 were also recorded under the same experimental condition described above. The following results were obtained: 1) In furosemide solution, pK1=3.8 (COOH group) and pK2=7.5 (NH group) were clearly demonstrated. 2) The buffering action of metal-furosemide solution was also demonstrated near pH of pK2. 3) A red shift of the color of CuCl2 -furosemide solution was observed near pH of pK2. The following conclusions were reached: 1) Furosemide could make a metal-chelating bond with Cu, Mg or Zn ion. Bonding ratio seemed to be 1, an intramolecular metal chelation would be made between NH group and COOH group. 2) Log Kc was estimated to be 3.72. A metal-chelating ability seemed to be an essential physico-chemical property of thiazide and its related diuretics. Though Kc of furosemide value was lower than that of thiazide diuretics already reported by the authors, a metal-chelate complex formation of furosemide under a physiological pH would have an important role on its pharmacological action.
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Studies on a Metal-helating Action of Furosemide

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