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Kinetics of Cyclophosphamide Biotransformation In vivo¹

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

The presence of therapeutically significant amounts of 4-hydroxycyclophosphamide-aldophosphamide in the blood of cyclophosphamide treated female C 57BL x DBA/2F₁ mice was established by cochromatography of the isolated semicarbazone derivative with authentic aldophosphamide semicarbazone. The kidneys of these mice had been functionally removed before the administration of cyclophosphamide by tying off the renal arteries and veins. Radiochromatography was utilized for quentification. The total amount of radioactivity present in the blood reached a maximum within 30 min after cyclophosphamide administration and remained at that level throughout the remainder of the 4-hr observation period. The blood concentration of 4-hydroxycyclophosphamide-aldophosphamide reached a maximum of approximately 50 nmol/ml (about 15% of the total radioactivity present in the blood) between 5 and 30 min after the i.p. administration of cyclophosphamide, 65 mg/kg. 4-Hydroxycyclophosphamide-aldophosphamide was rapidly converted to carboxyphosphamide; concomitant with the appearance of carboxyphosphamide was a fall in blood 4-hydroxycyclophosphamide-aldophosphamide concentration to less than 3% of the total radioactivity present 90 min after cyclophosphamide administration. Relative to 4-hydroxycyclophosphamide-aldophosphamide and carboxyphosphamide concentrations, the maximum amounts of all other metabolites found in the blood were small. These observations do not support the view that 4-hydroxycyclophosphamide-aldophosphamide is converted to other metabolites at the site of its formation so that it never enters the circulation in appreciable amounts. Rather, they support the contention that 4-hydroxycyclophosphamide-aldophosphamide serves as a transport form of the ultimate cytotoxic metabolite(s) of cyclophosphamide.

¹ Supported by USPHS Grants GM 15477 and CA 21737. A description of this investigation has also appeared in a thesis (6) submitted by B. E. Domeyer, in 1977 to the Department of Pharmacology, University of Minnesota, Minn., in partial fulfillment of the requirements for the Ph.D. degree. This is Paper 6 in a series on "Cyclophosphamide Metabolism."

² Present address: The Procter and Gamble Co., Miami Valley Laboratories, P. O. Box 39175, Cincinnati, Ohio 45247.

³ Research Career Development Awardee of the National Cancer Institute, USPHS (1-KO4-CA70383). To whom requests for reprints should be addressed, at 105 Millard Hall, 435 Delaware Street S. E., Minneapolis, Minn. 55455.

Received 4/ 2/79. Accepted 10/12/79.