Disposition kinetics and metabolism of nicotine-1'-N-oxide in rabbits

The disposition kinetics and metabolism of nicotine-1'-N-oxide (NNO) are of interest as the reduction of NNO might influence the pharmacokinetics of nicotine in tobacco users. The disposition kinetics of nicotine-1'-N-oxide were characterized in New Zealand rabbits. The clearance of NNO averaged 7.5 ml/min/kg. The half-life averaged 42.6 min and VDss was 0.34 liter/kg. The oral and ip bioavailabilities were 15.1 and 79%, respectively. NNO was reduced to nicotine and cotinine following i.v., oral, and ip injection. The pattern of metabolites after iv dosing suggests that there is systemic reduction of NNO, although the magnitude of that reduction is small, with less than 3% reduced to nicotine. Following oral NNO, 45% was reduced, with a metabolite pattern consistent with presystemic (bacterial or intestinal) metabolism.