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Mechanism of Action

Chlorambucil, an aromatic nitrogen mustard derivative, is an alkylating agent. Chlorambucil interferes with DNA replication and induces cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Pharmacokinetics

In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose-adjusted (±SD) plasma chlorambucil Cmax was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng.h/mL, the mean elimination half-life (t½) was 1.3 ± 0.5 hours, and the Tmax was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard (PAAM), the mean dose-adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng.h/mL, mean t½ was 1.8 ± 0.4 hours, and the Tmax was 1.9 ± 0.7 hours.

After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours.

Absorption

Chlorambucil is rapidly and completely ( > 70%) absorbed from the gastrointestinal tract. 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 to 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 Tmax by 2-fold and reduced the dose-adjusted Cmax and AUC values by 55% and 20%, respectively.

Distribution

The apparent volume of distribution averaged 0.31 L/kg following a single 0.2 mg/kg oral dose of chlorambucil in 11 cancer patients with chronic lymphocytic leukemia.

Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined.

Metabolism

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite undergo oxidative degradation to monohydroxy and dihydroxy derivatives.

Excretion

After a single dose of radiolabeled chlorambucil (¹⁴C), approximately 20% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard.

Last reviewed on RxList: 11/10/2011
This monograph has been modified to include the generic and brand name in many instances.