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Two kinds of dosage forms (tablets and retarded capsules) of furosemide (F) were compared in vitro dissolution profile and in vivo absorption studies. The dissolution of F from retarded capsules was extremely restricted in the first fluid of the JP XII disintegration test (within 0.8%), while the dissolution of F from tablets and retarded capsules in the second fluid of JP XII disintegration test were both complete. Metabolite specific assay of F showed F, conjugation of F with glucuronic acid (FG) and acyl migration isomers of FG (FG-iso) in urine or plasma. The mean cumulative urinary excretion of F following administration of the tablets during 24 h was twice that of retarded capsules. The mean area under the plasma concentration-time curve (AUC) of F following administration of tablets was 1.5 times that of retarded capsules. The mean cumulative urine volume during 24 h, however, was not significantly different between the two dosage forms. Clockwise hysteresis relationships between the diuretic response and the urinary excretion rate of F was observed after administration of retarded capsules. A straight relation between logarithm of the diuresis and logarithm of the urinary excretion of F was observed after maximum excretion rate of F following administration of both dosage forms.

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.