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Cyclophosphamide Metabolism in Children¹

Departments of Child Health [S. M. Y., M. C., L. P., R. W., M. J. T., A. D. J. P.], Pharmacogenetics Research Unit [S. M. Y., A. V. B., J. R. I.], and Medical Statistics [M. C.], The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH United Kingdom

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation 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 dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.

¹ This investigation was supported by The Tyneside Leukaemia Research Fund, The North of England Children's Cancer Research Fund, and The North of England Cancer Research Campaign.

² To whom requests for reprints should be addressed.

³ Present address: The Cancer Research Unit, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Received 8/22/94. Accepted 12/14/94.

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