The alkylating agent cyclophosphamide is a prodrug which is metabolize
d in vivo to produce both therapeutic and toxic effects. Cyclophospham
ide metabolism was investigated in 36 children with various malignanci
es. Concentrations of cyclophosphamide and its principal metabolites w
ere measured in plasma and urine using a quantitative high-performance
TLC method. The results indicated a high degree of inter-patient vari
ation in metabolism. In contrast to previous adult studies on urinary
metabolites, plasma carboxyphosphamide concentrations did not support
the existence of polymorphic metabolism. Plasma concentrations of dech
lorethylcyclophosphamide and carboxyphosphamide were correlated in ind
ividual patients, suggesting that the activity of both aldehyde dehydr
ogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide pro
duction in vivo, The presence of ketocyclophosphamide in plasma was st
rongly associated with dexamethasone pretreatment and was also accompa
nied by a high clearance of the parent drug. Interpatient differences
in metabolism reflect individual levels of enzyme expression and may c
ontribute to variation in clinical effect.