Cyclophosphamide - How It Works
Clinical pharmacology details from the US FDA-approved label: how Cyclophosphamide works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action The mechanism of action is thought to involve cross-linking of tumor cell DNA.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action is thought to involve cross-linking of tumor cell DNA.
12.2 Pharmacodynamics 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.
12.3 Pharmacokinetics 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 g/m 2 over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.
Absorption After oral administration, peak concentrations of cyclophosphamide occurred at one hour.
Area under the curve ratio for the drug after oral and IV administration (AUC po : AUC iv ) ranged from 0.87 to 0.96.
Distribution 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).
Metabolism 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.
4hydroxycyclophosphamide 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.
Pharmacokinetics
12.3 Pharmacokinetics 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 g/m 2 over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug. Absorption After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUC po : AUC iv ) ranged from 0.87 to 0.96. Distribution 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). Metabolism 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. 4hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can u