Detoxification of urotoxic oxazaphosphorines by sulfhydryl compounds

Abstract

Urotoxic side effects, especially hemorrhagic cystitis, have so far been a limiting factor in the therapeutic use of cyclophosphamide (Endoxan), ifosfamide (Holoxan), and trofosfamide (Ixoten). The uroprotective agent mesna (Uromitexan) allows regional detoxification in the kidneys and the urinary tract, and thus clinical prevention of the urotoxic side effects of the above cytostatics. The uroprotective mechanism of mesna is based on the formation of nontoxic additive compounds with acrolein and 4-hydroxy-metabolites. In the body, mesna is rapidly transformed into its biologically inert disulfide. After glomerular filtration mesna disulfide is rapidly reduced by reacting with the glutathion system and elimination in the urine as a free thiol compound, further detoxifying the aggressive oxazaphosphorine metabolites.