MOA and metabolism of cyclophosphamide
Cyclophosphamide is an inactive prodrug that is activated by hepatic cytochrome P-450 enzymes. Genetic polymorphisms of cytochrome P-450 enzymes can affect response to cyclophosphamide. The major active metabolite is phosphoramide mustard, which alkylates DNA and results in crosslinking of DNA, breaks in DNA, decreased DNA synthesis, and apoptosis. Cyclophosphamide synthesis has a marked effect on rapidly dividing cells and throughout the cell cycle, resulting in alterations in humoral and cellular immunity (B > T cells).
Liver disease does not increase the toxicity of cyclophosphamide. Initial dose is decreased by 30% if CrCl <30 cc/minute. Cyclophosphamide is dialyzable and should be administered more than 12 hours before a dialysis or administered any time after dialysis.
Acrolein is a major metabolic product of cyclophosphamide metabolism. It is responsible for causing hemorrhagic cystitis and bladder cancer.