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 furalt adone (5-morpholinomethyl- 3-[5-nitrofurfurylidene-amino]-2-oxazolidin one) by pig hepatocytes was shown to result from the N-oxidation of th e tertiary nitrogen in the morpholino-ring, leaving the nitrofuran rin g unchanged. 2. No evidence could be obtained for the formation of an open-chain cyano-metabolite, a minor metabolite in the case of the rel ated nitrofuran drug furazolidone 5-nitro-2-furfurylidene)-3-amino-2-o xazolidinone). This metabolite was the major metabolite, following inc ubation of furaltadone and furazolidone with Salmonella typhimurium ba cteria. 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 mu g/plate. Furaltadone gav e a positive result at 10 ng/plate. 4. The biotransformation of both d rugs by pig hepatocytes and bacteria resulted in the formation of prot ein-bound metabolites, with no clear quantitative differences between the two drugs. The intact 3-amino-2-oxazolidinone (AOZ) and 5-morpholi nomethyl-3-amino-2-oxazolidinone (AMOZ) side-chains of furazolidone an d furaltadone, respectively, could be released from these metabolites by mild acid treatment. 5. Hepatocytes incubated with the AMOZ side-ch ain of furaltadone showed a decreased monoamine oxidase activity at hi gh dose levels (IC50 3.7 mM), whereas exposure to the AOZ side-chain o f furazolidone resulted in a clear inhibition at 10 000-fold lower con centrations (IC50 0.5 mu M). In the presence of 1% dimethylsulphoxide (DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably r educed. 6. It is concluded that protein-bound metabolites containing a n intact and releasable side-chain might be present in tissues of anim als treated with furaltadone. However, these residues might be of less toxicological concern than those of furazolidone.