Sekikawa H, Yagi N, Lin E T, Benet L Z
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan.
Biol Pharm Bull. 1995 Jan;18(1):134-9. doi: 10.1248/bpb.18.134.
The stability of furosemide glucuronide (FG) was investigated in buffer solutions ranging from pH 1 through 10. This glucuronic acid conjugate was the major metabolite of furosemide (F) excreted in human urine. FG, obtained by extraction from human urine, was purified by ion-exchange chromatography. The concentration of FG, acyl migration isomers of FG (FG-iso), and F were determined simultaneously with an HPLC method that included fluorescence detection and gradient elution. FG was found to be unstable in highly acidic and in neutral to alkaline solutions. Hydrogen ion and hydroxy ion catalyzed the hydrolysis of FG below pH 2.8 and above pH 5.6, respectively. Above pH 3.7, FG instability led to the formation of eight FG-iso compounds. Though beta-glucuronidase cleaved FG, the FG-iso compounds were resistant to the enzyme. The half-life of FG in a buffer solution at pH 7.4 and 37 degrees C was 4.4 h. The maximum stability of FG (half-life about 62 d) occurred at approximately pH 3.2. Below pH 3.7, acyl migration products of FG were not detected. Instead, the hydrolysis of FG to F and glucuronic acid was followed by the formation of 4-chloro-5-sulfamoylanthranilic acid (CSA), a secondary product in acidic media.
在pH值为1至10的缓冲溶液中研究了呋塞米葡糖苷酸（FG）的稳定性。这种葡糖醛酸共轭物是呋塞米（F）在人尿中排泄的主要代谢产物。通过从人尿中提取获得的FG，经离子交换色谱法纯化。采用包括荧光检测和梯度洗脱的高效液相色谱法同时测定FG、FG的酰基迁移异构体（FG-iso）和F的浓度。发现FG在高酸性以及中性至碱性溶液中不稳定。氢离子和氢氧根离子分别在pH 2.8以下和pH 5.6以上催化FG的水解。在pH 3.7以上，FG的不稳定性导致形成8种FG-iso化合物。虽然β-葡糖醛酸酶可裂解FG，但FG-iso化合物对该酶具有抗性。FG在pH 7.4和37℃的缓冲溶液中的半衰期为4.4小时。FG的最大稳定性（半衰期约62天）出现在约pH 3.2处。在pH 3.7以下，未检测到FG的酰基迁移产物。相反，FG水解为F和葡糖醛酸后，在酸性介质中会形成次级产物4-氯-5-氨磺酰基邻氨基苯甲酸（CSA）。
