METABOLISM OF DEUTERATED ANALOGS OF CHLORAMBUCIL BY THE RAT

The antitumour agent chlorambucil {4[4-bis(2-chloroethyl)aminophenyl]butyric acid} is converted by β-oxidation in vivo into phenylacetic mustard {2[4-bis(2-chloroethyl)aminophenyl]acetic acid}. This process may be disadvantageous from a therapeutic viewpoint since the metabolite has half the therapeutic index of the parent drug against the Walker 256 carcinoma in rats. In seeking to retard β-oxidation, selectively deuterated analogues have been synthesised and administered to rats. Plasma levels of phenylacetic mustard after giving chlorambucil-β-d2 were lower than those given by unlabelled drug, but the therapeutic activity was not significantly altered by deuteration. A dehydro derivative of chlorambucil was detected as an intermediate in the β-oxidation pathway. The isotopic compositions of this metabolite, and of recovered chlorambucil, were measured in plasma samples taken after giving labelled chlorambucil (α-d2 and β-d2 variants) to rats. Deuterium was almost totally lost from the α-d2 form and from its metabolite after 30 min and partially lost in 10 min. The β-d2 variant and its dehydro-derivative retained the label. Possible mechanisms for deuteration loss are discussed. The design of novel analogues, based on these metabolic studies, is proposed. © 1979.