Identification of conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide.
Conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide were identified primarily by high-pressure liquid chromatography in combination with field desorption mass spectrometry. The spontaneous metabolic pathway of the drug, as related to its susceptibility to nucleophilic attack by endogenous thiols at the 9-carbon atom of the acridine moiety, has been studied. Among the metabolite fraction of 4'-(9-acridinylamino)methanesulfon-m-anisidide excreted in rat bile after administration of a therapeutic dose, a conjugate was identified as the 9-acridinyl thioether of glutathione. This conjugation product and the corresponding 9-acridinyl conjugates were formed spontaneously after incubation of 4'-(9-acridinylamino)methanesulfon-m-anisidide with glutathione, cysteine and N-acetylcysteine in sodium phosphate buffer and other aqueous media, as established by high-pressure liquid chromatography and field desorption mass spectra. The thiolytic pathway results in the release 4-amino-3-methoxymethanesulfonanilide which was identified in all in vitro experiments and in rat serum after intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide. 9(10H)-Acridone, 9-aminoacridine and other acridine derivatives which occur as minor products during the thiolytic cleavage in vitro were identified by field desorption and partially by high resolution electron impact mass spectrometry.
D000609:Aminoacridines / Q000008:administration & dosage / Q000032:analysis* / Q000378:metabolism; D000677:Amsacrine; D000818:Animals; D000970:Antineoplastic Agents; D001646:Bile / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002855:Chromatography, Thin Layer; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains
D000609:Aminoacridines; D000970:Antineoplastic Agents; D000677:Amsacrine; D005978:Glutathione