A C-13 NMR-STUDY OF 2-C-13-CHLOROACETALDEHYDE, A METABOLITE OF IFOSFAMIDE AND CYCLOPHOSPHAMIDE, IN THE ISOLATED-PERFUSED RABBIT HEART MODEL- INITIAL OBSERVATIONS ON ITS CARDIOTOXICITY AND CARDIAC METABOLISM

The metabolism of 2-C-13-chloroacetaldehyde at doses of 1.5, 2, 3 and 4 mg/kg b.w. and that of 2-C-13-chloroacetate at a dose of 5.9 mg/kg b .w. were studied in the isolated perfused rabbit heart model using car bon-13 nuclear magnetic resonance. We have shown that, whereas chloroa cetaldehyde is cardiotoxic at doses above 2 mg/kg b.w., this toxic eff ect is not accompanied by an increase in intramyocardial citrate level s. Chloroacetate, its main metabolite, is not cardiotoxic. The metabol ism of chloroacetaldehyde is complex and leads, in addition to chloroa cetate, to chloroethanol, glycolic acid, conjugates of glutathione wit h chloroacetate or chloroethanol (and/or their metabolites, S-(2-carbo xymethyl) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine, S-(2-hydrox yethyl) cysteine) and thiodiglycolic acid. Low amounts of chloroacetat e are metabolized by isolated perfused rabbit hearts into glycolic aci d and glutathione conjugate (and/or its metabolites, S-(2-carboxymethy l) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine). The present resul ts suggest the need to evaluate further the role that chloroacetaldehy de may play in the cardiotoxic effects of ifosfamide and cyclophospham ide.