1,3-dipalmitoylglycerol ester of chlorambucil as a lymphotropic, orally administrable antineoplastic agent.
A glyceride derivative of chlorambucil (2), 1,3-dipalmitoyl-2-[4-[bis (2-chloroethyl)amino]benzenebutanoyl]glycerol (1), was synthesized and tested as an orally administrable antineoplastic drug endowed with lymphotropic properties. A significantly higher efficacy (increased life span) and a reduced toxicity of 1, relative to 2, were apparent when both compounds given per os were evaluated against P388 leukemia subcutaneously implanted in mice, a situation where the tumor cells disseminate along the lymphatic route. In order to assess the selective absorption of 1 by the intestinal lymphatic system after oral administration, we determined plasma and intestinal lymphatic concentrations and compared them with that obtained with 2. The results clearly demonstrate that the esterification of 2 to a diacylglycerol moiety brings about considerably higher levels in the lymph and reduces plasma levels. Moreover, pharmacokinetic and biological data suggest that 1 is most probably acting by itself rather than as a prodrug of chlorambucil.
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007941:Leukemia P388 / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D002699:Chlorambucil; C038730:1,3-dipalmitoyl-2-(4-(bis(2-chloroethyl)amino)benzenebutanoyl)glycerol