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Cytotoxic Activity Relative to 4-Hydroxycyclophosphamide and Phosphoramide Mustard Concentrations in the Plasma of Cyclophosphamide-treated Rats¹

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

Male rats were given cyclophosphamide (50 mg/kg, i.p.), and the plasma concentrations of 4-hydroxycyclophosphamide and phosphoramide mustard were determined. Apparent plasma half-lives were 30 and 55 min, respectively. Area under the plasma concentration-time curve values were 1.5 and 2.5 mM·min, respectively. Since the plasma half-life of cyclophosphamide in rats is about 37 min, it may be that the actual plasma half-lives of the two metabolites are substantially shorter than the apparent plasma half-lives that were observed following cyclophosphamide administration would indicate, i.e., that the major determinant with regard to their apparent half-lives is the rate of cyclophosphamide hydroxylation rather than their rate of removal. Plasma cytotoxic activity was also determined after cyclophosphamide administration. A bioassay using cultured W256 tumor cells was used for this purpose, and the concentrations of 4-hydroxycyclophosphamide or phosphoramide mustard required to reproduce the observed cytotoxic activity were calculated. Good correlation between the actual and calculated concentrations of 4-hydroxycyclophosphamide was observed at all time points. In contrast, the actual levels of phosphoramide mustard were much too low to account for the observed cytotoxic activity. These observations support the contention that circulating 4-hydroxycyclophosphamide accounts for the bulk of the cytotoxic activity of cyclophosphamide towards W256 cells. Moreover, they predict that, in the rat, the important circulating metabolite will be 4-hydroxycyclophosphamide when the sensitivity of the tumor cells to 4-hydroxycyclophamide greatly exceeds that to phosphoramide mustard, and that it will be phosphoramide mustard when the reverse is the case. Since area under the plasma concentration-time curve values for 4-hydroxycyclophosphamide and phosphoramide mustard are also approximately equal following cyclophosphamide administration to mice or humans, similar predictions can be made for these species. Finally, since most experimental tumors are more sensitive to 4-hydroxycyclophosphamide than they are to phosphoramide mustard, and since highly favorable oncotoxic specificity has been demonstrated only with the former, we conclude that 4-hydroxycyclophosphamide is also likely to be the important circulating metabolite in those cancer patients where cyclophosphamide is of therapeutic value.

¹ Supported by USPHS Grants CA 26357 and CA 21737. A description of parts of this investigation has appeared in abstract form (24); a full description appears in a thesis submitted by J. F. Powers (19) in 1981 to the Department of Pharmacology, University of Minnesota, Minneapolis, in partial fulfillment of the requirements for the Ph.D. degree. This is the 12th in a series of papers on cyclophosphamide metabolism.

² Present address: The Procter & Gamble Company, Winton Hill Technical Center, 6110 Center Hill Road, Cincinnati, Ohio 45224.

³ To whom requests for reprints should be addressed, University of Minnesota, Department of Pharmacology, 3-260 Millard Hall, 435 Delaware Street S.E., Minneapolis, Minn. 55455.

Received 6/14/82. Accepted 12/ 7/82.