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The in vivo activation of cyclophosphamide (Endoxan) to cytostatic and alkylating metabolites has been studied. Endoxan is metabolized to the weak anion by microsomal dealkylation in the rat's liver; this product is the first alkylating metabolite. About 80% of the alkylating activity of the serum, occurring 30 min after injection of Endoxan is presented by this primary alkylating metabolite. Nor-N-mustard and N-2-chloroethyl-aziridine were found only in traces. Although some activation was detected in the liver, the lungs and to a minor extent the kidneys, this phenomenon has not been detected in the screened experimental rat tumors. The authors conclude that the greater specificity of Endoxan as compared to other cytostatic agents of the N-mustard group may be due to some specific permeation properties of the primary alkylating metabolite of Endoxan rather than to a possible specific mechanism of action of this compound within tumor cells.
Brock et al. (Sun,) studied this question.