The oxazaphosphorines including
cyclophosphamide (CPA),
ifosfamide (IFO), and
trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an
immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to
bone marrow transplantation for
aplastic anemia,
leukemia, and other
malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include
mafosfamide (NSC 345842),
glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard),
NSC 612567 (
aldophosphamide perhydrothiazine), and
NSC 613060 (
aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used
alkylating agents) and the clinical implications. Both CPA and IFO are
prodrugs that require activation by hepatic
cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic
nitrogen mustards capable of reacting with
DNA molecules to form crosslinks and lead to cell apoptosis and/or
necrosis. Such
prodrug activation can be enhanced within
tumor cells by the CYP-based gene directed-
enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as
glufosfamide,
NSC 612567 and
NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both
NSC 612567 and
NSC 613060 can be activated by plain
phosphodiesterase (
PDEs) in plasma and other tissues or by the high-affinity nuclear
3'-5' exonucleases associated with
DNA polymerases, such as
DNA polymerases and epsilon. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct
chloroacetaldehyde (CAA). Various
aldehyde dehydrogenases (ALDHs) and
glutathione S-
transferases (
GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the
orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and
drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as
breast cancer resistance
protein (BCRP),
multidrug resistance associated proteins (
MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and
tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing
enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in
cancer chemotherapy.