Cyclophos Mechanism of Action

Pharmacotherapeutic group: Antineoplastic and Immunomodulating Agents; Antineoplastic agents. Alkylating agents. Nitrogen mustard analogues.
Pharmacology: Pharmacodynamics: Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types.
500 mg: 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.
1 g: 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.
Mechanism of Action: Cyclophosphamide belongs to the group of alkylating agents which binds to DNA usually via the binding of alkyl groups. As a result, a reactive intermediary is formed which binds to DNA and causes single or double stranded DNA break and may crosslink the chains of DNA thus, disturbing the fundamental mechanisms concerned with cell growth, mitotic activity, differentiation and function. The effects of the alkylating agent although dependent on proliferation, are not cell cycle specific and hence the drug may act on cells at any stage of cycle.
Pharmacokinetics: 500 mg: Cyclophosphamide is administered as an inactive prodrug that is activated in the liver.
Absorption: Cyclophosphamide is quickly and almost completely absorbed from parenteral sites.
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 found 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 it 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.
1 g: Cyclophosphamide is absorbed from the gastrointestinal tract and from parenteral application sites. It is well absorbed after oral administration with a bioavailability greater than 75%. Peak levels are reached 1-3 hrs. after oral administration. The unchanged drug has an elimination half-life of 3-12 hrs. Several cytotoxic and non-cytotoxic metabolites have been identified in urine and in plasma. Concentration of drug reaches a maximum in plasma 2-3 days after an I.V. dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent of 60%. The distributing volume is about 0.69 L/kg indicating that Cyclophosphamide is distributed in all body fluids including the brain (CSF). Cyclophosphamide is capable of crossing the placental barrier. It is also found in the breastmilk. Total body-clearance of Cyclophosphamide is approximately 82 mL/min and by hepatic metabolism. Only 13% of Cyclophosphamide is excreted unchanged in urine. Metabolites are ultimately eliminated primarily by kidneys, the main urinary metabolite being carboxyphosphamide.