Biotransformation of furaltadone by pig hepatocytes and Salmonella typhimurium TA 100 bacteria, and the formation of protein-bound metabolites.
1. The major metabolite resulting from the biotransformation of furaltadone (5-morpholinomethyl-3-[5-nitrofurfurylidene-amino]-2-oxazoli dinone) by pig hepatocytes was shown to result from the N-oxidation of the tertiary nitrogen in the morpholino-ring, leaving the nitrofuran ring unchanged. 2. 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. 3. 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 microgram/plate. Furaltadone gave a positive result at 10 ng/plate. 4. 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-oxazolidinone (AMOZ) side-chains of furazolidone and furaltadone, respectively, could be released from these metabolites by mild acid treatment. 5. 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 microM). In the presence of 1% dimethylsulphoxide (DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably reduced. 6. 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.
State Institute for Quality Control of Agricultural Products (RIKILT-DLO), Wageningen, The Netherlands.
L A
LA
Hoogenboom
T H
TH
Polman
A
A
Lommen
M B
MB
Huveneers
J
J
van Rhijn
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism; D009152:Mutagenicity Tests; D009581:Nitrofurans / Q000493:pharmacokinetics* / Q000633:toxicity; D023303:Oxazolidinones; D011485:Protein Binding; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism*; D013055:Spectrophotometry, Infrared; D013552:Swine
D000892:Anti-Infective Agents, Urinary; D008996:Monoamine Oxidase Inhibitors; D009581:Nitrofurans; D023303:Oxazolidinones; C007795:furaltadon