Leukeran Mechanism of Action

Antineoplastic and immunomodulating agents, antineoplastic agents, alkylating agents, nitrogen mustard analogues. ATC Code: L01AA02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. In addition to interference with DNA replication, chlorambucil induces cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of an apoptosis promoter (Bax).
Pharmacodynamic Effects: The cytotoxic effect of chlorambucil is due to both chlorambucil and its major metabolite phenylacetic acid mustard (see Pharmacokinetics as follows).
Mechanism of Resistance: Chlorambucil is an aromatic nitrogen mustard derivative and resistance to nitrogen mustards has been reported to be secondary to: alterations in the transport of these agents and their metabolites via various multi-resistance proteins, alterations in the kinetics of the DNA cross-links formed by these agents and changes in apoptosis and altered DNA repair activity. Chlorambucil is not a substrate of multi-resistant protein 1 (MRP1 or ABCC1), but its glutathione conjugates are substrates of MRP1 (ABCC1) and MRP2 (ABCC2).
Pharmacokinetics: Absorption: Chlorambucil is well absorbed by passive diffusion from the gastrointestinal tract and is measurable within 15-30 minutes of administration. The bioavailability of oral chlorambucil is approximately 70% to 100% following administration of single doses of 10-200 mg.
In a study of 12 patients administered approximately 0.2 mg/kg bodyweight of oral chlorambucil, the mean dose adjusted maximum plasma concentration (492 ± 160 ng/ml) occurred between 0.25 and 2 hours after administration.
Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2-4 fold interpatient variability in AUC).
The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median time to reach C_max by greater than 100%, reduced the peak plasma concentration by greater than 50% and reduced mean AUC (0-∞) by approximately 27% (see Dosage & Administration).
Distribution: Chlorambucil has a volume of distribution of approximately 0.14-0.24 L/kg. Chlorambucil covalently binds to plasma proteins, primarily to albumin (98%), and covalently binds to red blood cells.
Biotransformation: Chlorambucil is extensively metabolised in the liver by monodichloroethylation and β-oxidation, forming phenylacetic acid mustard (PAAM) as the major metabolite, which possesses alkylating activity in animals. Chlorambucil and PAAM degrade in vivo forming monohydroxy and dihydroxy derivatives. In addition, chlorambucil reacts with glutathione to form mono- and diglutathionyl conjugates of chlorambucil.
Following the administration of approximately 0.2 mg/kg of oral chlorambucil, PAAM was detected in the plasma of some patients as early as 15 minutes and mean dose adjusted plasma concentration (C_max) of 306 ± 73 nanograms/mL occurred within 1 to 3 hours.
Elimination: The terminal phase elimination half-life ranges from 1.3-1.5 hours for chlorambucil and is approximately 1.8 hours for PAAM. The extent of renal excretion of unchanged chlorambucil or PAAM is very low; less than 1% of the administered dose of each of these is excreted in the urine in 24 hours, with the rest of the dose eliminated mainly as monohydroxy and dihydroxy derivatives.
Toxicology: Pre-clinical Safety Data: Mutagenicity and Carcinogenicity: As with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
Reproductive Toxicology: In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
Teratogenicity: Chlorambucil has been shown to induce developmental abnormalities, such as short or kinky tail, microcephaly and exencephaly, digital abnormalities including ectro-, brachy-, syn- and polydactyly and long-bone abnormalities such as reduction in length, absence of one or more components, total absence of ossification sites in the embryo of mice and rats following a single oral administration of 4 to 20 mg/kg. Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3 to 6 mg/kg.
Brain and Plasma Pharmacokinetics: After oral administration of 14C-marked chlorambucil to rats, the highest concentrations of radioactive marked material were found in the plasma, in the liver and in the kidneys. Only small concentrations were measured in the cerebral tissue of rats after intravenous administration of chlorambucil.