title: Comparative metabolism of 2-[bis(2-chloroethyl)amino]tetrahydro-2-H-1,3,2-oxazaphosphorine-2-oxide (cyclophosphamide) and its enantiomers in humans.
abstract: The comparative metabolism of the enantiomers of cyclo phosphamide and of the racemate has been 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 hr) of unchanged drug and of two enzymatically produced metabolites, 4-ketocyclophosphamide and carboxyphosphamide, were determined using mass spectrometry-stable isotope dilution. There was no significant difference between the three 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 either racemic or only slightly enriched in the (-)-enantiomer. The two 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.
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D003520:Cyclophosphamide / Q000097:blood / Q000378:metabolism* / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D008175:Lung Neoplasms / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D013057:Spectrum Analysis
chemical_list: D003520:Cyclophosphamide