Metabolism of bumetanide.

The metabolism of bumetanide is reviewed, with emphasis on the relationship between metabolism and diuretic activity. Substantial evidence has been obtained for the thesis that diuretic activity is dependent on the amount of bumetanide which reaches the renal tubule. Therefore, bumetanide is a potent diuretic in those species, e.g., human and dog, in which a substantial fraction of the administered dose is excreted as unchanged drug in the urine. In contrast, relatively weak diuretic activity is seen in the rat, a species which very effectively biotransforms bumetanide to inactive metabolites. The metabolites which have been identified in human and rat urine are presented, and the point is made that in both species metabolism of bumetanide appears to be limited to oxidation of the N-butyl side chain. Different (and unidentified) metabolites are excreted by the dog. A prominent metabolite formed in the dog, however, is the acylglucuronide of bumetanide, which was detected in plasma and bile but was not seen in urine or feces. Tissue distribution of bumetanide in the dog is presented so as to show the ability of the kidney to concentrate bumetanide. In the human, bumetanide disposition is also characterized by 95 per cent plasma protein binding and a plasma half-life of 1 to 2 hours. Attention is given to the possibility that the clinical response to bumetanide can be altered by factors which affect drug oxidation by the mixed-function oxygenase system; e.g., induction of the drug-metabolizing enzymes may lead to increased biotransformation of bumetanide and concomitant decreased diuretic activity.