Metabolism of S-nicotine in noninduced and aroclor-induced rats

The urinary excretion of nicotine and its metabolites in noninduced and Aroclor-induced male and female rats has been determined following intravenous administration of 2'-[14C]-labeled S-nicotine at a dose of 4.6 mumol/kg. Complete recovery of the administered radioactivity was achieved: 95% in urine and 4% in feces over 96 h and 1% remaining in the body. More than 40 nicotine metabolites were found by radio-HPLC; 19 were identified including the cis/trans-diastereomers of nicotine-N'-oxide and 3'-hydroxycotinine. The urinary metabolite profile and excretion kinetics of nicotine and its metabolites were significantly different between noninduced and Aroclor-induced rats. The major urinary nicotine metabolite in the noninduced rat was cis-nicotine-N'-oxide. In the Aroclor-induced rat, cotinine metabolites were the major metabolites found. Sex differences were found for the urinary nicotine metabolite profile, mainly expressed in the excretion of cis-nicotine-N'-oxide, 29% in the male and 17% in the female noninduced rat, and the excretion of cotinine, 5% in the male and 12% in the female noninduced rat. High stereoselectivity was found for the formation of the cis/trans-diastereomers of nicotine-N'-oxide as well as of 3'-hydroxycotinine, the stereoselectivity being more pronounced in male rats.