Application of deuterium labelling mass spectrometry in a study of the metabolism of the enantiomers of cyclophosphamide

P. J. Cox, P. B. Farmer, A. B. Foster, L. J. Griggs, M. Jarman, R. Kinas, K. Pankiewicz, W. J. Stec

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22 Scopus citations

Abstract

The antitumour agent cyclophosphamide—{2‐[bis(2‐chloroethyl)amino]‐tetrahydro‐2H ‐1,3,2‐oxaza‐phosphorine 2‐oxide}—is chiral owing to asymmetry at phosphorus. The differential metabolism of the enantiomers [(+)‐cyclophosphamide and (−)‐cyclophosphamide] can be monitored by mass spectrometry if pseudoracemates consisting of either unlabelled [2H0] (+)‐ and tetradeuterated [2H4] (−)‐cyclophosphamide or of [2H0](−) and [2H4](+) enantiomers are administered. Using this principle, methodology has been developed for determining the enantiomer ratios of cyclophosphamide and two metabolites, 4‐ketocyclophosphamide {2‐[bis(2‐chloroethyl)amino] tetrahydro‐2H‐1,3,2‐oxazaphosphorin‐4‐one 2‐oxide} and carboxyphosphamide [2‐carboxyethyl N,N‐bis(2‐chloroethyl)phosphorodiamidate] recovered from the urine of mice. The drug and the two metabolites were quantified using [2H10]cyclophosphamide, 4‐keto‐[2H8]cyclophosphamide and [2H6]carboxyphosphamide respectively, as internal standards. The amount of cyclophosphamide excreted was small and neither enantiomer preponderated markedly, but the minor metabolite, 4‐ketocyclophosphamide, was markedly depleted in the enantiomer derived from (−)‐cyclophosphamide, whereas the major metabolite, carboxyphosphamide, was slightly depleted in the enantiomer derived from (+)‐cyclophosphamide.

Original languageEnglish (US)
Pages (from-to)371-375
Number of pages5
JournalBiological Mass Spectrometry
Volume4
Issue number6
DOIs
StatePublished - Dec 1977

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