An Overview of Cyclophosphamide and Ifosfamide Pharmacology

Abstract

Cyclophosphamide and ifosfamide are alkylating agents administered to treat malignant disease. They are prodrugs and require activation by hepatic microsomal enzymes before being metabolized to their respective cytotoxic species, phosphoramide mustard and ifosfamide mustard. These species alkylate DNA, forming DNA‐DNA cross‐links that result in inhibition of DNA synthesis and cell death. Resistance to oxazaphosphorines is poorly understood, although increased aldehyde dehydrogenase activity may be a significant factor. Although both compounds share a common metabolic pathway, 4‐hydroxylation of ifosfamide occurs at a slower rate and to a lesser extent than that of cyclophosphamide. This difference significantly alters the toxicity profile of ifosfamide. Leukopenia is the dose‐limiting toxicity of cyclophosphamide, and neurotoxicity is the dose‐limiting toxicity of ifosfamide when preventive measures are taken to reduce urotoxicity. With recent findings concerning their basic and clinical pharmacology, the therapeutic index of these compounds can be improved.

DNA Adducts in Cancer Chemotherapy

“…Oxazaphosphorines, including cyclophosphamide 13 and ifosfamide 14 , are a class of phosphoramide mustards that require metabolic activation to exert their anticancer activities. As illustrated in Figure , these drugs undergo α-hydroxylation of the phosphoramide moiety mediated by cytochrome P450s . The resulting metabolites, 4-hydroxycyclophosphamide 36 and 4-hydroxyifosfamide 45 , are in equilibrium with their ring-open form aldophosphamides 37 and 46 , which spontaneously decompose to release acrolein 39 and the active forms 40 and 47 .…”

“…As illustrated in Figure 3, these drugs undergo α-hydroxylation of the phosphoramide moiety mediated by cytochrome P450s. 27 The resulting metabolites, 4-hydroxycyclophosphamide 36 and 4-hydroxyifosfamide 45, are in equilibrium with their ring-open form aldophosphamides 37 and 46, which spontaneously decompose to release acrolein 39 and the active forms 40 and 47. However, if the P450s-catalyzed hydroxylation occurs to the α-carbon of the 2-chloroethylamino group, as illustrated by the formation of 42, 48, and 49, chloroacetaldehyde 44 and monoalkylating metabolites such as 43 and 50 are formed.…”