Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention—I: Experimental studies on the urotoxicity of alkylating compounds

Abstract

The urotoxic potency of various (mainly alkylating) drugs was studied in an extensive series of experiments. It was found that damage to the kidneys and to the efferent urinary tract (haemorrhagic cystitis) is a specific side effect of compounds possessing the oxazaphosphorine ring. This effect is due to the renal excretion of toxic metabolites. The only carriers of urotoxicity are the renally eliminated fractions of the 4-hydroxy-oxazaphosphorines and acrolein which is formed spontaneously therefrom. Other oxazaphosphorine metabolites and breakdown products such as the directly alkylating phosphoric acid diamides, 4-keto-derivatives and carboxyderivatives, have at most only a very slight urotoxic potency. The relationships between the chemical structure and the urotoxicity have been clarified in the group of oxazaphosphorines. Using a standardised test model (rat) the urotoxic side effects of cytostatics were studied experimentally and were measured quantitatively. The urotoxic effects were found to be dose- and concentration-dependent and also showed a marked dependence on the pH. The manifestations of inflammation were more pronounced in an alkaline than in an acidic milieu.