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Mechanism of Action
The mechanism of action is thought to involve cross-linking of tumor cell DNA.
Cytoxan (cyclophosphamide) is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells.
Following IV administration, elimination half-life (t ½) ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h. Pharmacokinetics are linear over the dose range used clinically. When cyclophosphamide was administered at 4.0 g/m² over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.
After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUCpo : AUCiv) ranged from 0.87 to 0.96.
Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L).
The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t1/2 values following repeated administration at 12- to 24-hour interval.
Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.
The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group, (Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of < 10mL/min) compared to the control group. The increase in exposure was significant in the severe group (p > 0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see Use In Specific Populations].
The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 reported in uremic patients. Reduction in t1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable.
Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t½) is prolonged by 64%. Mean CL and t½ were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group [see Use in Specific Populations].
Last reviewed on RxList: 6/13/2013
This monograph has been modified to include the generic and brand name in many instances.
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