Cyclophosphamide Other names: Cytophosphane

Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types. The active metabolites of cyclophosphamide are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.

Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types.

Cyclophosphamide engages probably to the S-or G2-phase of the cell cycle.

It remains to be shown whether the cytostatic effect is entirely dependent on the alkylation of DNA or other mechanisms such as inhibition of chromatin transformation processes or inhibition of DNA polymerases play a role. The metabolite acrolein has no antineoplastic activity, but is responsible for the adverse urotoxic effect.

The immunosuppressive effect of cyclophosphamide is based on the fact that cyclophosphamide has an inhibitory effect on B-cells, CD4 + T-cells and to a lesser extent on CD8 +- T-cells. In addition, it is assumed that cyclophosphamide has an inhibitory effect on the suppressor that regulate the IgG2 class of antibodies.

Cross-resistance, especially with structurally related cytotoxic agents, e.g. ifosfamide, as well as other alkylating agents, cannot be excluded.

Cyclophosphamide is administered as an inactive prodrug that is activated in the liver.

Absorption

Cyclophosphamide is well absorbed following an oral dose with a mean half-life of 4-8 hours for both oral and parenteral administration.

Distribution

Less than 20% of cyclophosphamide is bound to plasma proteins. The protein binding of the metabolites of cyclophosphamide is higher but less than 70%. To what extent the active metabolites protein bound, is not known.

Cyclophosphamide is about in the cerebrospinal fluid and the mother’s milk. Cyclophosphamide and metabolites can pass through the placenta.

Metabolism

Cyclophosphamide is activated in the liver to the active metabolites 4-hydroxy-cyclophosphamide and aldofosfamide (tautomeric form of 4-hydroxy-cyclophosphamide) through phase I metabolism by cytochrome P450 (CYP) enzymes. Different CYP isozymes contribute to the bioactivation of cyclophosphamide, including CYP2A6, 2B6, 2C9, 2C19 and 3A4, 2B6 in which the exhibits highest 4-hydroxylase activity. Detoxification is done mainly through glutathione-S-transferases (GSTA1, GSTP1) and alcohol dehydrogenase (ALDH1, ALDH3). Two to four hours after administration of cyclophosphamide, the plasma concentrations of the active metabolites are maximal, after which a rapid decrease of plasma concentrations takes place.

Elimination

The plasma half-life of cyclophosphamide is about 4 to 8 hours in adults and children. The plasma half-lives of the active metabolites are not known.

Following high-dose IV administration within the framework of allogeneic bone marrow transplantation, the plasma concentration of pure cyclophosphamide follows linear first- order kinetics. Compared with conventional cyclophosphamide therapy, there is an increase in inactive metabolites, indicating saturation of activating enzyme systems, but not of the stages of metabolism leading to inactive metabolites. During the course of high-dose cyclophosphamide therapy over several days, there is a decrease in the areas under the plasma concentration-time curve of the parent compound, probably due to auto-induction of microsomal metabolism activity.

Cyclophosphamide and its metabolites are primarily excreted by the kidneys.

Acute toxicity

The acute toxicity of cyclophosphamide is relatively low. This was demonstrated in studies on mice, guinea pigs, rabbits and dogs.

Chronic toxicity

Chronic administration of toxic doses led to hepatic lesions manifested as fatty degeneration followed by necrosis. The intestinal mucosa was not affected. The threshold for hepatotoxic effects was 100 mg/kg in the rabbit and 10 mg/kg in the dog.

Mutagenicity and carcinogenicity

The mutagenic effects of cyclophosphamide have been demonstrated in various in-vitro and in-vivo tests. Chromosome aberrations following administration of cyclophosphamide have also been observed in humans. The carcinogenic effects of cyclophosphamide have been demonstrated in animal studies on rats and mice.

Teratogenicity

The teratogenic effects of cyclophosphamide have been demonstrated in various animals (mice, rats, rabbits, rhesus monkeys and dogs). Cyclophosphamide can cause skeletal, tissue as well as other malformations.