Biotransformation of furaltadone by pig hepatocytes and Salmonella typhimurium TA 100 bacteria, and the formation of protein-bound metabolites

• Published in: Xenobiotica Vol. 24; no. 8; pp. 713 - 727
• Main Authors: Hoogenboom, L.A.P, Polman, T.H.G, Lommen, A, Huveneers, M.B.M, Rhijn, J. van
• Format: Journal Article
• Language: English
• Published: England 1994
• Subjects: Animals; Anti-Infective Agents, Urinary - pharmacokinetics; Anti-Infective Agents, Urinary - toxicity; biochemical pathways; Biotransformation; Cells, Cultured; Chromatography, High Pressure Liquid; Female; furaltadone; furazolidone; hepatocytes; in vitro; Liver - metabolism; Magnetic Resonance Spectroscopy; metabolism; metabolites; Monoamine Oxidase Inhibitors - metabolism; mutagenicity; Mutagenicity Tests; Nitrofurans - pharmacokinetics; Nitrofurans - toxicity; Oxazolidinones; Protein Binding; Salmonella typhimurium; Salmonella typhimurium - genetics; Salmonella typhimurium - metabolism; Spectrophotometry, Infrared; Swine; toxicology
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498259409043272

The major metabolite resulting from the biotransformation of furaltadone (5-morpholinomethyl-3-[5-nitrofurfurylidene-amino]-2 oxazolidinone) by pig hepatocytes was shown to result from the N-oxidation of the tertiary nitrogen in the morpholino-ring, leaving the nitrofuran ring unchanged. No evidence could be obtained for the formation of an open-chain cyano-metabolite, a minor metabolite in the case of the related nitrofuran drug furazolidone (N-(5-nitro-2-furfurylidene)-3-amino-2-oxazolidinone). This metabolite was the major metabolite, following incubation of furaltadone and furazolidone with Salmonella typhimurium bacteria. The N-oxide was not further metabolized by pig hepatocytes or bacteria, and gave negative test results in the Ames-test (TA 100, no S9-mix) at the highest tested dose of 1 micogram/plate. Furaltadone gave a positive result at 10 mg/plate. The biotransformation of both drugs by pig hepatocytes and bacteria resulted in the formation of protein-bound metabolites, with no clear quantitative differences between the two drugs. The intact 3-amino-2-oxazolidinone (AOZ) and 5-morpholinomethyl-3-amino-2-oxazoiidinone (AMOZ) side-chains of furazolidone and furaltadone, respectively, could be released from these metabolites by mild acid treatment. Hepatocytes incubated with the AMOZ side-chain of furaltadone showed a decreased monoamine oxidase activity at high dose levels (IC50 3.7 mM), whereas exposure to the AOZ side-chain of furazolidone resulted in a clear inhibition at 10 000-fold lower concentrations (IC50 0.5 micromoles). In the presence of 1% dimethylsulphoxide (DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably reduced. It is concluded that protein-bound metabolites containing an intact and releasable side-chain might be present in tissues of animals treated with furaltadone. However, these residues might be of less toxicological concern than those of furazolidone.