Comparative brain and plasma pharmacokinetics and anticancer activities of chlorambucil and melphalan in the rat

Equimolar doses of chlorambucil and melphalan (both 10 mg/kg) were administered i.v. to anesthetized rats, and the plasma and brain concentrations of chlorambucil, its metabolites 3,4-dehydrochlorambucil and phenylacetic mustard, and melphalan were determined by high-performance liquid chromatography from 5 to 240 min thereafter. Chlorambucil demonstrated a monophasic disappearance from plasma, with a half-life of 26 min. The compound was 99.6% plasma-protein-bound. Chlorambucil underwent beta-oxidation to yield detectable concentrations of 3,4-dehydrochlorambucil and substantial amounts of phenylacetic mustard in the plasma. Low concentrations of chlorambucil and phenylacetic mustard were detected in the brain. Calculated from the areas under the concentration-time curves, the brain:plasma concentration integral ratios of chlorambucil and phenylacetic mustard were 0.021 and 0.013, respectively. Melphalan demonstrated a biphasic disappearance from plasma, with half-lives of 1.9 and 78 min. The compound was approximately 86% plasma protein-bound. Low concentrations of melphalan were detected in the brain, and its brain:plasma ratio was 0.13. These data demonstrate that following the administration of chlorambucil and melphalan, only low concentrations of active drug are able to enter the brain. As a consequence, concentrations of both drugs that cause the complete inhibition of extracerebrally located tumor have no effect on those located within the brain. Further, the brain uptake of melphalan, although low, is greater than that of chlorambucil and its active metabolites, which coincides with its slightly greater intracerebral activity following the systemic administration of very high doses.