Cyclophosphamide

Cyclophosphamide is an inactive pro-drug, converted by the mixed function oxidase system in the liver to the alkylating agents 4-hydroxy-cyclophosphamide and phosphoramide mustard, which alkylate guanine nucleotides, thus blocking cell division (20). Bioavailability after oral administration is greater than 75%, but there are large variations between individuals in the rate of production of active metabolites. A phenotypic variation in carboxylator activity affects the production of the inactive metabolite carboxyphosphoramide from 4-hydroxy-cyclophosphamide, which may influence efficacy and toxicity. The relation of renal and hepatic failure to the production and elimination of active metabolites has not been fully determined. Bladder toxicity is caused by renal excretion of the metabolite acrolein which can cause haemorrhagic cystitis and a markedly increased risk of bladder cancer (20). Other adverse effects include nausea and vomiting, myelosuppression with neutropenia, infections due to immunosuppression (4), alopecia and infertility. Permanent ovarian failure occurs in over 50% of women after one year’s exposure and is age-related; male infertility has been less well studied. The incidence of leukaemia and /or lymphoma is increased tenfold; less common adverse effects include pulmonary fibrosis, hepatitis and the syndrome of inappropriate ADH secretion.