in vivo nitrosation of amidopyrine in humans: use of ‘ethanol effect’ for biological monitoring of N-nitrosodimethylamine in urine

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Abstract
Under normal conditions a possible N-nitrosodimethylamine formation in vivo cannot directly be monitored in urine due to high metabolic conversion rate (>99.9%). Own experiments showed an increased excretion rate (up to 2.4%) if ethanol was administered simultaneously. This model was used for monitoring experiments with repect to in vivo for mation of N-nitrosodimethylamine. Amidopyrine, as a compound which is easily nitrosated, was administered (single oral dose of 500 mg) to volunteers. Under the influence of 20–30 g ethanol it was possible to detect N-nitrosodimethylamine in urine. From negative control experiments it must be concluded that this appearance of N-nitrosodimethylamine derives from in vivo nitrosation of the drug. The amount excreted in urine varied between 0.5 and 10 μg N-nitrosodimethylamine within 8 h and seemed to be influenced by salivary nitrite concentrations which ranged from 5 to 220 p.p.m. NO2−. In comparison with earlier excretion studies in humans it can be assumed that only 1–2% of the originally formed nitrosamine was found in urine. To our knowledge this is the first time that in vivo formation of N-nitrosodimethylamine was directly shown to occur in humans.