Identification of the principal biliary metabolite of 4'-(9-acridinylamino)methanesulfon-m-anisidide in rats

Journal Article · · Drug Metab. Dispos.; (United States)

OSTI ID:6656163

Shoemaker, D D; Cysyk, R L; Padmanabhan, S; Bhat, H B; Malspeis, L

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 D/sub 2/O 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 MnO/sub 2/ to -methanesulfonyl - - (9-acridinyl)-3'-methoxy - 2',5' - cyclohexadiene-1',4'-diimine (m-AQDI) followed by reaction of m-AQDI with glutathione. The /sup 1/H-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.

• Research Organization: Laboratory of Chemical Pharmacology, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD
• OSTI ID: 6656163
• Journal Information: Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 10:1; ISSN DMDSA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ANIMALS
ANTINEOPLASTIC DRUGS
BILIARY TRACT
BIOCHEMICAL REACTION KINETICS
DIGESTIVE SYSTEM
DRUGS
GLUTATHIONE
KINETICS
LABELLED COMPOUNDS
MAGNETIC RESONANCE
MAMMALS
METABOLISM
METABOLITES
NUCLEAR MAGNETIC RESONANCE
ORGANIC COMPOUNDS
PEPTIDES
PHARMACOLOGY
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RATS
REACTION KINETICS
RESONANCE
RODENTS
VERTEBRATES