DRUG STUDY AND INFORMATION FORMGeneric Name: Cyclophosphamide (Nitrogen Mustard)

Trade Name: Cytoxan, Endoxan

Drug Class: Alkylating Agents and Platinum Coordination Complexes

Structure/Chemistry: Platinum alkylating complex

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Mechanism of Action: The platinum complexes form covalent metal adducts through crosslinks with intra- and interstand DNA at guanine N7 positions. Cyclophosphamide travels to tumor cells as aldophosphamide where it cleaves spontaneously producing phophoramide mustard and acrolein. Phoshoramide mustard is responbile for antitumor effects while acrolein causes hemorrhagic cystitis (reduced by mesna).

Pharmacologic Effects: Induces cell cycle arrest through extensive DNA damage. Apoptosis of the cell is dependent on an intact p53 response and the abilities of the DNA repair systems. Causes cell death in rapidly proliferating tissues.

Drug Resistance or Tolerance: Develops rapidly when used as a single agent. Resistance due to decreased permeation of actively transported drugs, increased intracellular concentrations of nucleophilic substances (thiols such as glutathione that can conjugate with and detoxify intermediates), increased activity of DNA repair pathways, increased degradation of activated forms, detoxification by glutathione transferases, loss of ability to recognize adducts as the result of defective MMR, and impaired apoptotic pathways

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Absorption: Absorbed well orally given daily at a dose of 100 mg/m2 for 14 days (patients with lymphomas or CLL) or given by IV at higher doses of 500 mg/m2 every 2-4 weeks (breast cancer and lymphomas). Vigorous IV hydration during high-dose treatment to prevent bladder toxicity.

Distribution:

Elimination: t1/2 of 7 hours. Maximal plasma concentration reached at 1 hour. Degraded by host aldehyde dehydrogenase, aldehyde oxidase, and glutathione transferase.

Metabolism: Metabolically activated through hydroxylation by CYP2B to 4-hydroxycyclophosphamide. Patients more severe hepatic dysfunction with serum bilirubin >3 mg/dL should receive reduced dosages.

Adverse Side Effects/Toxicity: Myelosuppression, oral mucosal ulceration, intestinal denudation, alopecia, nausea, and vomitting. Discontinue if hematuria is present. Inappropriate secretion of antidiuretic hormone. Following high-dose therapy, GI ulceration, cystitis, and less commonly, pulmonary, renal, hepatic, and cardiac toxicities. May induce sterility, teratogenic effects, and leukemia.

Drug Interactions:

Therapeutic uses: Cancer—non-Hodgkin’s lymphomas, other lymphoid malignancies, Burkitt’s lymphomas, breast and ovarian cancers, and solid tumors in children.Immunosuppression—auto-immune disorders

Miscellaneous: