Nitrosation of piperazine in man

Piperazine, a secondary amine used as an anthelmintic drug, nitrosates rapidly in vitro to form two nitrosamines. Anhydrous piperazine and a drug formulation were found to have a content of 0.2-20 micrograms of the suspected carcinogen, N-mononitrosopiperazine, per gram of piperazine, but no detectable amount of the carcinogen, N,N'-dinitrosopiperazine. The possible nitrosation of the drug piperazine in man was investigated, with the following results. Thirty min after oral administration of 480 mg piperazine to four, fasting, healthy, male volunteers, gastric juice contained 0.14-0.23 micrograms/mL N-mononitrosopiperazine, as determined by gas chromatography-thermal energy analysis. The total amount produced in the stomach is estimated to have been 30-66 micrograms. The nitrosamine was not detected in blood, but was excreted in the urine, mainly during the first 8 h (0.8-2.5 micrograms). Half had appeared within 3 h. Acidification of the urine did not affect the excretion. N,N'-Dinitrosopiperazine was never found in gastric juice, blood or urine. Co-administration of 2 g ascorbic acid resulted in a significant, but incomplete and varying, inhibition of nitrosation in the stomach and of nitrosamine excretion in the urine.