In vitro studies on the hydrolysis of frusemide in gastrointestinal juices.

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Abstract
To elucidate a possible explanation for a relatively low bioavailability, the hydrolysis of frusemide in gastrointestinal juices was studied in vitro at concentrations likely to be present in vivo. Between 1.0 and 4.4% of the frusemide molecules were hydrolyzed to 4‐ chloro‐N‐furfuryl‐5‐sulphamoyl‐antranilic acid (CSA) after 1 h at 37 degrees C in gastric juices. The rate of hydrolysis was inversely connected to pH. No fall in frusemide concentration was observed and no CSA was found in duodenal juices after 4 h at 37 degrees C. In three buffer solutions with the same pH as three gastric juices frusemide was hydrolyzed to CSA at a lower rate than in the gastric juices (pH 1.2, P less than 0.15;pH 1.4, P less than 0.001; pH 1.6, P less than 0.001). The solubility of frusemide was significantly higher in gastric juice from two fasting subjects (83‐104 mg l‐1) than in buffer solutions with the same pH (52‐58 mg 1‐1). The solubility of frusemide was significantly increased (by 40‐50%) in gastric juice obtained after pentagastrin stimulation compared with its solubility in the mixed gastric secretion obtained after fasting. The binding of frusemide to macromolecules was 28.0 +/‐ 9.7% in ventricular secretion after fasting while it was 1.4 +/‐ 2.6% in the fluid obtained after pentagastrin stimulation. It is concluded that a hydrolysis of frusemide in the stomach prior to absorption cannot explain the relatively low bioavailability of the drug observed after oral intake.