COMPARATIVE METABOLISM OF 2-[BIS(2-CHLOROETHYL)AMINO]TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORINE-2-OXIDE (CYCLOPHOSPHAMIDE) AND ITS ENANTIOMERS IN HUMANS

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (7) , 2762-2767
Abstract
The comparative metabolism of the enantiomers of cyclophosphamide [an antineoplastic drug] and of the racemate was studied in humans. Four patients were each given, sequentially, the racemate, the (+)-enantiomer, and its (-)-antipode. The plasma levels of parent drug and the urinary output (24 h) of unchanged drug and of 2 enzymatically produced metabolites, 4-ketocyclophosphamide and carboxyphosphamide, were determined using mass spectrometry-stable isotope dilution. There was no significant difference between the 3 forms of cyclophosphamide with respect to plasma half-life (.beta. phase) or in the urinary outputs of the drug or of carboxyphosphamide. The output of 4-ketocyclophosphamide after administration of (+)-cyclophosphamide was significantly greater than that produced from the racemate. Cyclophosphamide recovered from the urine of patients given the racemate was eithr racemic or only slightly enriched in the (-)-enantiomer. The 2 enantiomers were almost equally bound to plasma protein. Based on these metabolic studies alone, there is little reason to predict that the enantiomers will differ from each other or from the racemate in their therapeutic effects in humans, but there are other factors, e.g., stereoselective uptake of the intermediary 4-hydroxylated metabolites by neoplastic cells, which could elicit such differences.