Cytotoxic activity relative to 4-hydroxycyclophosphamide and phosphoramide mustard concentrations in the plasma of cyclophosphamide-treated rats

Powers, J.F.; Sladek, N.E.

Cancer Research 43(3): 1101-1106

1983


ISSN/ISBN: 0008-5472
PMID: 6825082
Accession: 005083085

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Abstract
Male rates were given cyclophosphamide (CP) (50 mg/kg, i.p.), and the plasma concentrations of 4-hydroxycyclophosphamide (HCP) and phosphoramide mustard (PM) 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 .cntdot. min, respectively. Since the plasma half-life of CP in rats is about 37 min, it may be that the actual plasma half-lives of the 2 metabolites are substantially shorter than the apparent plasma half-lives that were obesrved following CP administration would indicate, i.e., that the major determinant with regard to their apparent half-lives is the rate of CP hydroxylation rather than their rate of removal. Plasma cytotoxic activity was also determined after CP administration. A bioassay using cultured W256 tumor cells was used for this purpose, and the concentrations of HCP or PM required to reproduce the observed cytotoxic activity were calculated. Good correlation between the actual and calculated concentrations of HCP was observed at all time points. In contrast, the actual levels of PM were much too low to account for the observed cytotoxic actiivty. Circulating HCP probably accounts for the bulk of the cytotoxic activity of CP towards W256 cells. These observations predict that, in the rat, the important circulating metabolite will be HCP when the sensitivity of the tumor cells to HCP greatly exceeds that to PM and that it will be PM when the reverse is the case. Since area under the plasma concentration-time curve values for HCP and PM are also approximately equal following CP administration to mice or humans, similar predictions can be made for these species. Finally, since most experimental tumors are more sensitive to HCP than they are to PM, and since highy favorable oncotoxic specificity has been demonstrated only with the former, HCP is also likely to be the important circulating metabolite in those cancer patients where CP is of therapeutic value.