The Chemistry of the Metabolites of Cyclophosphamide

This is primarily an overview of the spontaneous (non-enzymatic) chemistry of the metabolites of cyclophosphamide, viz., cis- and trans-4-hydroxycyclophosphamide, aldophosphamide (and its hydrate), iminophosphamide, phosphoramide mustard, acrolein, and chloroethylaziridine. A brief description of detoxification products obtained through enzyme catalyzed reactions appears. Included as the historical basis for the development of cyclophosphamide is the chemistry of nitrogen mustards. Among the topics covered are: perturbations to metabolite distributions and half-lives effected by buffer, structure, pH and nucleophiles; effects of pH on mechanism; alkylation versus P-N bond hydrolysis; the influence of nucleophiles on alkylation product distributions; the influence of substituents on alkylation rates; and preactivated forms of cyclophosphamide as metabolite precursors (4-hydroperoxycyclophosphamide and mafosfamide). A review with 66 references.