[Pharmacokinetics of cyclophosphamide and cyclophosphamide metabolites in the mouse and their influence on the therapeutic effect of "activated" cyclophosphamide (4-hydroxycyclophosphamide) (author's transl)].

Therapy tests with 2- [bis(2-chloroethyl)amino]tetrahydro (2H)-1,3,2-oxazaphosphorinane-2-oxide (cyclophosphamide (CP)) and its metabolites 4-hydroxycyclophosphamide (4-OH-CP) and phosphoramide mustard (NLDP) were carried out on heterotransplanted human breast cancer in nude mice. The results are: 1. Only 4-hydroxycyclophosphamide can imitate the therapeutic effect of cyclophosphamide. 2. The therapeutic effect is not proportional to the product of concentration and time (cXt) in blood as tumor growth was more inhibited with lower cXt when high concentrations were present over a short time than with higher cXt and adjustment of low concentrations over a long time. Pharmacokinetic measurements in mice demonstrated that this behaviour is due to the elimination of "activated" cyclophosphamide by Michaelis-Menten kinetics (Km = 146 nmol X ml-1, Vmax = 18 nmol X ml-1 X min-1) and to the fact that increasing blood concentration of "activated" cyclophosphamide is accompanied by its increased distribution towards the peripheral compartment as may be seen from the volumes of distribution of the peripheral and central compartments. From blood concentration curves of cyclophosphamide and cyclophosphamide metabolites we calculated that 91% of the cyclophosphamide administered is activated. 81% of the "activated" cyclophosphamide is detoxified to 4-keto-CP and carboxyphosphamide (Carboxyph). Since the detoxifying enzymatic system is more active against aldophosphamide than against 4-hydroxycyclophosphamide the non-detoxified rest of "activated" cyclophosphamide is composed of 80% of 4-hydroxycyclophosphamide and 20% of aldophosphamide.