The absorption and first-pass metabolism of [14C]-1,3-dinitrobenzene in the isolated vascularly perfused rat small intestine.
We tested the hypothesis that the small intestine is capable of the first-pass, reductive metabolism of xenobiotics. A simplified version of the isolated vascularly perfused rat small intestine was developed to test this hypothesis with 1,3-dinitrobenzene (1,3-DNB) as a model xenobiotic. Both 3-nitroaniline (3-NA) and 3-nitroacetanilide (3-NAA) were formed and absorbed following intralumenal doses of 1,3-DNB (1.8 or 4.2 mumol) to isolated vascularly perfused rat small intestine. Dose, fasting, or antibiotic pretreatment had no effect on the absorption and metabolism of 1,3-DNB in this model system. The failure of antibiotic pretreatment to alter the metabolism of 1,3-DNA indicated that 1,3-DNB metabolism was mammalian rather than microfloral in origin. All data from experiments initiated with lumenal 1,3-DNB were fit to a pharmacokinetic model (model A). ANOVA analysis revealed that dose, fasting, or antibiotic pretreatment had no statistically significant effect on the model-dependent parameters. 3-NA (1.5 mumol) was administered to the lumen of isolated vascularly perfused rat small intestine to evaluate model A predictions for the absorption and metabolism of this metabolite. All data from experiments initiated with 3-NA were fit to a pharmacokinetic model (model B). Comparison of corresponding model-dependent pharmacokinetic parameters (i.e. those parameters which describe the same processes in models A and B) revealed quantitative differences. Evidence for significant quantitative differences in the pharmacokinetics or metabolism of formed versus preformed 3-NA in rat small intestine may require better definition of the rate constants used to describe tissue and lumenal processes or identification and incorporation of the remaining unidentified metabolites into the models.
Adams
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Curriculum in Toxicology, University of North Carolina, Chapel Hill, USA.
Rickert
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D000083:Acetanilides / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D004136:Dinitrobenzenes / Q000378:metabolism* / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D000083:Acetanilides; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D004136:Dinitrobenzenes; C104137:3-nitroacetanilide; C008625:nitroaniline; C017906:3-dinitrobenzene