title: Involvement of glutathione in the metabolism of the anilinoacridine antitumour agents CI-921 and amsacrine.
abstract: 4'-(9-Acridinylamino)methanesulphon-m-anisidide (amsacrine) and CI-921, the 4-methyl-5-(N-methyl-carboxamide) derivative of amsacrine, are two anilinoacridine antitumour agents in clinical use or trial. The elimination of these agents has been investigated in male BDF1 mice. 74% and 86% of the dose of [acridinyl-G-3H]-amsacrine and -CI-921, respectively, was excreted in the faeces of mice by 72 hr after i.v. injection. Administration of both compounds also resulted in significant depletion of glutathione (GSH) in mouse liver, although the effect of CI-921 was delayed and reduced compared with amsacrine. In mouse bile, radiolabelled products which cochromatographed with amsacrine GSH conjugates at both the 5'- and 6'-positions of the anilino ring were present in similar amounts and constituted approximately 70% of the excreted radioactivity, the balance being minor, more polar metabolites. With hepatic microsomal fractions, both conjugates of amsacrine were formed but only the 6'- and not the 5'-conjugate was increased in the presence of cytosol. Preliminary evidence indicates the presence in mouse bile of at least the 5'-GSH conjugate of CI-921, and several other GSH derived products not seen with amsacrine. It is concluded that the elimination of CI-921 occurs by a mechanism similar to that of amsacrine. Further, the possible involvement of GSH transferase in the conjugation of amsacrine may have consequences for the hepatotoxicity of this agent.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
authors.forename: I G
authors.initials: IG
authors.lastname: Robertson
authors.forename: P
authors.initials: P
authors.lastname: Kestell
authors.forename: R A
authors.initials: RA
authors.lastname: Dormer
authors.forename: J W
authors.initials: JW
authors.lastname: Paxton
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D005243:Feces / Q000032:analysis; D005978:Glutathione / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D000677:Amsacrine; D005978:Glutathione; C042315:asulacrine