METABOLISM OF S-NICOTINE IN NONINDUCED AND AROCLOR-INDUCED RATS

The urinary excretion of nicotine and its metabolites in noninduced an d Aroclor-induced male and female rats has been determined following i ntravenous administration of 2'-[C-14]-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 exc retion kinetics of nicotine and its metabolites were significantly dif ferent between noninduced and Aroclor-induced rats. The major urinary nicotine metabolite in the noninduced rat was cis-nicotine-N'-oxide. I n the Aroclor-induced rat, cotinine metabolites were the major metabol ites found. Sex differences were found for the urinary nicotine metabo lite profile, mainly expressed in the excretion of cis-nicotine-N-oxid e, 29% in the male arid 17% in the female noninduced mt, and the excre tion of cotinine, 5% in the male and 12% in the female noninduced rat. High stereoselectivity was found for the formation of the cis/trans-d iastereomers of nicotine-N'-oxide as well as of 3'-hydroxycotinine, th e stereoselectivity being more pronounced in male rats.