CYCLOPHOSPHAMIDE METABOLISM IN CHILDREN

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.