Identification of the principal biliary metabolite of 4'-(9-acridinylamino)methanesulfon-m-anisidide in rats.
m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide] labeled in either the acridine or anilino portion was used to investigate the disposition of this antitumor agent in rats. The principal biliary metabolite, which accounts for approximately 80% of the total biliary radioactivity for 90 min after administration and greater than 50% of the administered dose by 180 min after administration, had both the acridine and the anilino portions intact. Isolation and purification of the principal metabolite was achieved by preparative thin-layer chromatography on silica gel and column chromatography on Amberlite XAD-2 resin. A nuclear magnetic resonance (NMR) spectrum of the CID salt in D2O showed that the metabolite is the m-AMSA-glutathione conjugate in which the thioether linkage occurs at the 5'-position of the anilino ring. Synthesis of the metabolite was achieved by oxidizing m-AMSA with active MnO2 to -methanesulfonyl - - (9-acridinyl)-3'-methoxy - 2',5' - cyclohexadiene-1',4'-diimine (m-AQDI) followed by reaction of m-AQDI with glutathione. The 1H-NMR spectrum of the synthetic product proved identical with that of the isolated metabolite. The demonstration that the principal biliary metabolite on m-AMSA involves glutathione bound to the 9-anilino ring suggests that m-AMSA may be bioactivated in vivo to the quinoidal diimine, m-AQDI.
D000166:Acridines / Q000032:analysis; D000609:Aminoacridines / Q000378:metabolism*; D000677:Amsacrine; D000814:Aniline Compounds / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D055598:Chemical Phenomena; D002621:Chemistry; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000166:Acridines; D000609:Aminoacridines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D000677:Amsacrine; D005978:Glutathione