Comparative pharmacokinetics of chlorambucil and melphalan in man.

We have studied the pharmacokinetics of orally administered chlorambucil and melphalan in patients with hematologic malignancies and solid tumors. With a standard oral dose of 0.6 mg/kg, chlorambucil showed much more rapid systemic appearance than did melphalan and had a mean peak plasma concentration and area under the plasma disappearance curve which was 3-4 times greater than that observed in patients receiving melphalan. Melphalan had extremely variable systemic availability which was not observed with chlorambucil, and was not related to problems in tablet formulation. Chlorambucil undergoes extensive active metabolism to phenylacetic acid mustard, whereas melphalan undergoes rapid chemical degradation and has little, if any, active metabolism. On a pharmacokinetic basis, chlorambucil's greater in vitro stability, its more rapid and predictable systemic availability after oral dosing, and its extremely low urinary excretion make it a more predictable alkylating agent for clinical use than melphalan, especially for patients with reduced renal function.