Activation of cyclophosphamide in man and animals

Abstract

The authors studied the alkylating activity in the blood serum of man and rats after administration of cyclophosphamide, and its dependence on dosage. The alkylating activity was determined by means of the NBP test. For the process of activation, distribution in the body, and elimination, a mathematic model was developed and checked by means of the experimental data. The following results were obtained: 1. The cyclophosphamide activation curves studied for the doses of 15.6, 31.3, and 62.5 mg/kg are very constant in the rat, the NBP regression lines depending clearly on dosage. 2. The pharmacokietics of the metabolite level in man, studied for the doses of 30 and 60 mg/kg, show great individual fluctuations. But even here the dependence of the activity curves on dosage is statistically significant. 3. The average peaks of the metabolite level in man, related to the same dose, are about half to three quarters those found in the rat. 4. In man, the alkylating activity in the blood is detectable longer than in the rat. The values of the elimination constants in man are about two thirds of those in the rat. 5. Direct determination of the cyclophosphamide activation rate in liver sections of man and rats shows the activation rate in man related to the moist weight of the liver, to be‐even in vitro‐only about 60% of that of the rat. 6. Our findings show that there are no basic qualitative differences in cyclophosphamide activation between man and rat. They offer interesting aspects for the improvement of the therapeutic use of cyclophosphamide.

Cytotoxicity of cyclophosphamide in the rat incisor

“…The relative immunity of the odontogenic epithelium compared with the odontogenic mesenchyme to cytotoxic injury in the 40 mg group may thus be due to the difference in their mitotic indices (Chiba, 1965), to a difference in their permeability, biochemistry and biochemical activity or to all these factors. The evidence of some cytotoxic injury to the odontogenic epithelium and the increasing injury to the proliferating mesenchymal cells in the 80 mg and 120 mg groups may be related to the fact that, in the rat, the concentration and duration of cyclophosphamide in the tissues are directly related to the dose (Friedman, 1967;Brock et al, 1971). Thus, increasing dosage not only appears to affect increasing numbers of susceptible cells in any one group (Rall, 1967) but also a wider variety of cell populations (Stekar, 1973).…”

In vivo study of sister chromatid exchange and cellular kinetics in bone marrow cells of Rana catesbeiana.

“…In in-vivo test systems, positive results can be acquired without addition of microsomal enzymes. Species differences in their ability to activate cyclophosphamide were described (Brodk et al 1971). Comparison of the sensitivity of different species to sister chromatid exchange in duction by in vivo exposure to cyclophosphamide can be made.…”

Increase in the gastrointestinal absorption and in tissue storage of cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease

“…Whereas the plasma disappearance curve had indicated a rapid absorption of the drug with a peak at 15 min, the concentration of 14C in the kidneys, which constitute the principal excretory pathway for cyclophosphamide in several animal species (Torkelson et al, 1974) as in man (Bagley, Bostick and DeVita, 1973), would seem to indicate a rapid elimination. However, it had been noted that in mice (Torkelson et al, 1974) tion in the liver can be explained by the important role played by this organ in the biotransformation of cyclophosphamide into cytotoxic alkylating metabolites Hohorst, 1962, 1967;Cohen and Jao, 1970;Brock et al, 1971;Sladek, 1972). In mice, the initial oxidative step in cyclophosphamide metabolism is performed by the microsomal mixed function oxidase system of the liver to yield 4-hydroxy cyclophosphamide (Sladek, 1972) which is converted to aldophosphamide; aldophosphamide is very toxic to L-1210 leukaemia cells (Hill et al, 1972) and is further oxidized, probably by liver aldehyde oxidase, to carboxyphosphamide, a metabolite which has little or no anti-tumour effect on L-1210 cells (Hill et al, 1972).…”

“…Besides the fact that the drug must be metabolized by the liver before exerting its cytotoxic activity Hohorst, 1962, 1967;Cohen and Jao, 1970;Brock et al, 1971), other factors such as absorption and selective storage in some tissues might influence the quality and duration of cyclophosphamide activity.…”