Molecular Pharmacology, Vol 7, 519-529, Copyright © 1971 by the American Society for Pharmacology and Experimental Therapeutics

Urinary Metabolites of the Antitumor Agent Cyclophosphamide

¹ Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205

2-Carboxyethyl N, N-bis(2-chloroethyl)phosphorodiamidate and 4-ketocyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-4-one 2-oxide) have been isolated and identified as urinary metabolites of dogs treated with the anticancer agent cyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide). 2-Carboxyethyl N, N-bis(2-chloroethyl)phosphorodiamidate is the major urinary metabolite, whereas 4-ketocyclophosphamide is a minor metabolite and represents the first known product of cyclophosphamide which retains the ring structure. Another urinary metabolite yields -hydroxypropionamide on hydrolysis, a further indication that the primary oxidative step in the metabolism of cyclophosphamide occurs on carbon 4 of the ring. Neither of the two isolated metabolites is highly cytotoxic to human epidermoid cancer cells in vitro or to Leukemia L1210 cells in vivo. Neither compound is on a pathway leading to an active form of the drug.

Note:
ACKNOWLEDGMENTS We are very grateful to Miss D. Adamson and Mrs. M. H. Vail for performing the cytotoxicity studies with cloned cells. Dr. L. Wilkoff and Dr. F. Schabel of the Chemotherapy Department of Southern Research Institute determined the cytotoxicity tests in swirl cultures, with monolayers of cells, and with mice implanted with tumor cells. Human urine was obtained from patients at M. D. Anderson Hospital, Houston, through the courtesy of Dr. James Luce. Mr. T. C. Herren and Mr. H. E. Finch assayed samples for radioactivity. The microanalytical and spectral determinations were performed by Dr. W. C. Coburn, Jr., and associates. Some of the analyses were performed by Galbraith Laboratories, Knoxville, Tenn. We are indebted to Dr. N. Brock for a recent gift of a sample of synthetic 4-ketocyclophosphamide, and to Dr. A. Takamizawa for a sample of synthetic 2-carboxyethyl N,N-bis(2-chloroethyl)phosphorodiamidate.

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