A contribution to safety assessment of veterinary drug residues: in vitro/ex vivo studies on the intestinal toxicity and transport of covalently bound residues

1. The gastrointestinal fate of protein-bound residues of the model compoun d furazolidone (FZD) was investigated in vitro and ex vivo. Protein-bound r esidues were generated in rat liver microsomes, isolated by solvent extract ion and digested with 0.5 % hydrochloric acid and Pronase E. 2. During digestion, 3-amino-2-oxazolidinone (AOZ), the side chain of furaz olidone, was partly released from bound residues. 3. The absorption of free AOZ and digested protein-bound residues was teste d in isolated perfused rat gut segments (IPGS) and in the intestinal cell l ine Caco-2. Free AOZ was transfered both in the IPGS model and in Caco-2 mo nolayer cultures, while no indications for passage of bound residues were o btained. 4. No acute toxicity of AOZ or digested food residues respectively was obse rved in gut segments and Caco-2 cells at concentrations that were substanti ally above maximum residue levels to be expected in food of animal origin a fter administration of therapeutic doses. 5. The results demonstrate that digestive processes can alter the chemical nature of drug residues and yield degradation products that may be bioavail able for the consumer. Thus, the covalent binding of xenobiotics to macromo lecular tissue constituents cannot necessarily be regarded as an irreversib le endpoint of residue bioavailability and toxicity.