Pharmacokinetics of cyclophosphamide (Endoxan): The balance of cyclophosphamide metabolites in the mouse

With regard to the mechanism of action of cyclophosphamide some controversy exists whether 4-hydroxycyclophosphamide (“activated cyclophosphamide”) or phosphoramide mustard, a metabolite formed from it by ß-elimination of acrolein, is the therapeutically effective metabolite. In the following report, pharmacokinetic measurements after intravenous injection into the mouse show that 90% of cyclophosphamide administered is activated to 4-hydroxycyclophosphamide and that 80% thereof is detoxified to 4-ketocyclophosphamide and carboxyphosphamide. From therapy tests on heterotransplanted human breast cancers only 4-hydroxycyclophosphamide (liberated in vivo from cyclophosphamide) but not phosphoramide mustard, can imitate the therapeutic effects of cyclophosphamide. These results exlude the extracellular formation of phosphoramide mustard having a significant role in the therapeutic effects of cyclophosphamide.