title: Synthesis and in vivo biodisposition of [14C]-quaternary ammonium-melphalan conjugate, a potential cartilage-targeted alkylating drug.
abstract: For the purpose of developing more selective anticancer drugs that would concentrate in the malignant cartilaginous tumors (chondrosarcomas), and so improve therapeutic index through a reduction of side effects, a quaternary ammonium (QA) conjugate of melphalan was synthesized and labeled with (14)C by linking the QA moiety to nitrogen mustard via an amide bond. Comparative pharmacokinetic study of [(14)C]-melphalan and its [(14)C]-QA conjugate conducted on rats showed that the two compounds were principally excreted by the urinary way. The blood elimination of the QA conjugate was faster than that of the melphalan. In the other hand a higher rate of radioactivity derived of [(14)C]-MQA was found in feces. In the biodisposition for most organs, no striking differences were found between melphalan and its QA conjugate except for cartilages which exhibited more higher radioactivity level. Amounts of radioactivity derived from [(14)C]-QA conjugates measured in cartilaginous tissues until 1 h after injection demonstrate that the introduction of a QA moiety on melphalan allows the molecule to be carried selectively to cartilaginous tissues. As the [(14)C]-QA conjugate is radiolabeled on the chloroethyl alkylating moiety, levels of radioactivity measured in the cartilaginous tissues results from unchanged compound or metabolite having kept the active group.
authors.affiliation: INSERM UMR 484, Rue Montalembert, BP 184, 63005 Clermont-Ferrand Cedex, France. rapp@inserm484.u-clermont1.fr
authors.forename: Maryse
authors.initials: M
authors.lastname: Rapp
authors.forename: Isabelle
authors.initials: I
authors.lastname: Giraud
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Maurizis
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Galmier
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001345:Autoradiography; D002356:Cartilage / Q000378:metabolism*; D016503:Drug Delivery Systems; D005243:Feces / Q000737:chemistry; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D008466:Mechlorethamine / Q000737:chemistry; D008558:Melphalan / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007202:Indicators and Reagents; D000644:Quaternary Ammonium Compounds; D008466:Mechlorethamine; D008558:Melphalan