Intestinal first-pass metabolism of nitrosamines. 2. Metabolism of N-nitrosodibutylamine in isolated perfused rat small intestinal segments

In a previous study a high first-pass metabolism of N-nitrosodi-[1-¹⁴C]butylamine(NDBA, O.32–730p.µM) has been shown in isolatedperfused rat small intestinal segments. In the present workthe identification and quantitation of metabolitesin samplesof perfusate and absorbed fluid (absorbate) is reported. AfterHPLC enrichment and purification five metabolites could be identifiedby GLC-MS: N-nitrosobutyl-(3-hydroxybutyl)amine (NB3HBA), N-nitrosobutyl-(4-hydroxybutyl)amine(NB4HBA), N-nitrosobutyl-(3-carboxypropyl)amine (NB3CPA), N-nitrosobutyl-(2-hydroxy-3-carboxypropyl)amine(NB2H3CPA) and N-nitrosobutylcarboxymethylamine (NBCMA), representing> 95% of total metabolites. -hydroxylatlon leading to NB4HBAand NB3CPA accounted for 75–95% of total metabolites.The formation of their follow-up products NB2H3CPA and NBCMAwas too small for quantitative analysis. In absorbate NB3CPAwas by far the most important metabolite. The hydroxylationof NB4HBA to NB3CPA was more efficient in jejunal as comparedto ileal segments.-1-hydroxylation to NB3HBA and, as reportedpreviously, -hydroxylation were only minor metabolic pathways.In conclusion, a high first-pass metabolism of NDBA to the proximatebladder carcinogen NB3CPA takes place during its absorptionin rat small intestine. This is in contrast to the observationin rat liver preparations, where - and -1-hydroxylation arethe predominant pathways. The intestinal first-pass metabolismmay play a key role explaining the increased incidence of bladdertumors in rats after low oral doses of NDBA.