Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.