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.
Hoogenboom
L A
LA
State Institute for Quality Control of Agricultural Products (RIKILT-DLO), Wageningen, The Netherlands.
Polman
T H
TH
Lommen
A
A
Huveneers
M B
MB
van Rhijn
J
J
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