Leukeran Pharmacology, Pharmacokinetics, Studies, Metabolism - Chlorambucil

Leukeran Pharmacology, Pharmacokinetics, Studies, Metabolism - Chlorambucil

CLINICAL PHARMACOLOGY

Chlorambucil is rapidly and completely absorbed from the gastrointesinal tract. After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels are reached within 1 hour and the terminal half-life of the parent drug is estimated at 1.5 hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely low - less than 1% in 24 hours. The peak plasma levels of chlorambucil and phenylacetic acid mustard are similar, approximating 1 mcg/mL; however, the metabolite’s half-life is 1.6 times greater than that of the parent drug.

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. Evidence of human teratogenicity suggests that the drug crosses the placenta.

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil, approximately 15% 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. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.