Studies on the urinary metabolites of isophosphamide and its activated species in rabbits.

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Investigations on the urinary metabolites of isophosphamide, 4-hydroxyisophosphamide and 4-hydroxyisophosphamide including stereoisomers of the C4-oxidized derivatives in rabbits revealed that their metabolic behaviors were different from each other and also form those of cyclophosphamide. Administration of isophosphamide to rabbits resulted in the urinary excretion of carboxyisophosphamide and two N-dechloroethylated metabolites besides considerable amount of unchanged isophosphamide, while 4-hydroxyisophosphamide was metabolized principally into carboxyisophosphamide. In the case of 4-hydroxyisophosphamide, carboxyisophosphamide was excreted as a major metabolite, but considerable amount of a new metabolite which might be produced from 4-ketoisophosphamide via a hitherto unknown pathway was also excreted besides small amount of 4-ketoisophosphamide. Mechanism of the formation of this new metabolite was proposed based on the chemical conversion of a suggested intermediate into the metabolite. PHosphorus configuration of the C4-oxidized isophosphamides was found to have no significant effect upon their metabolism. It was suggested that the results of the present studies could account for the great differences in in vivo antitumor activities between isophosphamide and its pre-activated derivatives and also between isophosphamide and cyclophosphamide.

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