title: The metabolism of deuterated analogues of chlorambucil by the rat.
abstract: The antitumour agent chlorambucil (4[4-bis(2-chloroethyl)aminophenyl]-butyric acid) is converted by beta-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 beta-oxidation, selectively deuterated analogues have been synthesised and administered to rats. Plasma levels of phenylacetic mustard after giving chlorambucil-beta-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 beta-oxidation pathway. The isotopic compositions of this metabolite, and of recovered chlorambucil, were measured in plasma samples taken after giving labelled chlorambucil (alpha-d2 and beta-d2 variants) to rats. Deuterium was almost totally lost from the alpha-d2 form and from its metabolite after 30 min and partially lost in 10 min. The beta-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.
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium; D005260:Female; D009588:Nitrogen Mustard Compounds / Q000378:metabolism; D010648:Phenylacetates / Q000378:metabolism; D051381:Rats
chemical_list: D009588:Nitrogen Mustard Compounds; D010648:Phenylacetates; C008826:phenacid; D002699:Chlorambucil; C026365:3,4-dehydrochlorambucil; D003903:Deuterium