PHARMACOKINETICS AND METABOLISM OF CHLORAMBUCIL IN PATIENTS WITH MALIGNANT DISEASE

The distribution and excretion of oral (15-30 mg/m2) 14C-labelled chlorambucil has been determined in advanced cancer patients. Absorption was consistently rapid; the maximum concentration in plasma was reached between 40 and 70 minutes. After i.v. chlorambucil elimination of plasma radioactivity followed an open two compartment model. Analysis of whole blood extracts indicated two metabolites, chromatographically very similar, one of which was the product of β-oxidation of chlorambucil, 2-(4-bis(2-chlorethyl) aminophenyl) acetic acid, but the other was not identified. Urinary radioactivity following oral and i.v. administration suggested that after oral administration, absorption was complete. The bulk of radioactivity in the urine (>95% total) comprised metabolites more polar than chlorambucil. After i.v. administration early urine samples contained traces of metabolites (<5%) chromatographically indistinguishable from bis and mono 2-chloroethyl-2(4-aminophenyl) acetic acid. The oral route is not inferior to the i.v. route, and irrespective of route, the extent of metabolism is sufficient to allow the metabolite material to contribute significantly to the activity of the drug. © 1979 Academic Press.