Influence of diuretics on urinary general base catalytic activity and cyclophosphamide-induced bladder toxicity

The influence of diuretics on the induction of bladder toxicity by cyclophosphamide was investigated in rats. Following ip administration, about 3.5% of the cyclophosphamide was excreted as 4-hydroxycyclophosphamide. This amount was found to be compatible with the view that the urotoxic effects of cyclophosphamide are caused by the acrolein generated in the urine from 4-hydroxycyclophosphamide, the primary metabolite of cyclophosphamide. In situ, acrolein was more potent than 4-hydroperoxycyclophosphamide with regard to producing an increase in bladder weight; phosphoramide mustard was essentially without urotoxic activity. The urotoxic potency of 4-hydroperoxycyclophosphamide, but not that of acrolein, increased as the pH and/or the phosphate concentration of the infusion medium increased. This was as expected in view of the knowledge that release of acrolein from 4-hydroxycyclophosphamide or 4-hydroperoxycyclophosphamide is facilitated by the presence of general base catalysts, eg, phosphate and bicarbonate, and that the rate at which this reaction proceeds in the presence of these catalysts increases as their concentration and the pH increases. In vivo, diuretics that acidified the urine, eg, ammonium chloride and furosemide, prevented the increase in bladder weight ordinarily elicited by the dose of cyclophosphamide used in these experiments. In contrast, a diuretic, acetazolamide, that markedly increased urinary bicarbonate concentration and alkalinized the urine, did not. None of the diuretics altered the systemic metabolism and urinary excretion of cyclophosphamide nor did they alter the systemic action, as judged by spleen weight, of cyclophosphamide. These observations demonstrate that the pH of the urine and the urinary concentration of general base catalysts greatly influence the urotoxic potential of oxazaphosphorines such as cyclophosphamide. They indicate that while the use of acidifying diuretics is likely to be beneficial in minimizing oxazaphosphorine-induced bladder toxicity, the use of alkalinizing diuretics may not be helpful.