The quantitation by gas chromatography-chemical ionisation-mass spectrometry of cyclophosphamide, phosphoramide mustard and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy

Abstract

Cyclophosphamide, the widely used antitumour drug, is not itself toxic, but must be converted by microsomal metabolism to active metabolites. Despite an early understanding of the requirement for metabolic activation, the drug was used clinically for more than 10 years before the structures of any of its hepatic metabolites were elucidated. When the metabolites were finally isolated and identified, their characterisation rested heavily on mass spectral analysis (Bakke, Feil and Zaylskie, 1971; Colvin, Padgett and Fenselau, 1973; Struck et al., 1971). Subsequently mass spectrometry has been used in conjunction with stable-isotope labels to study the mechanism of alkylation of cytotoxic metabolites (Colvin et al., 1976) and for experiments with metabolic switching (Jarman et al., this volume pp. 85–95). Methodology has also been reported for assaying these cytotoxic metabolites using stable-isotope-labelled internal standards (Jardine et al., 1975, 1976; Jarman et al., 1975). In this report we will review the application of this methodology to assays of cyclophosphamide, phosphoramide mustard and nornitrogen mustard in blood and urine of patients, as well as in decomposition and protein-binding studies.