DISTRIBUTION AND RETENTION OF NICOTINE AND ITS METABOLITE, COTININE, IN THE RAT AS A FUNCTION OF TIME

Nicotine is oxidized to its major metabolite, cotinine, which has a lo ng biological half-life (19-24 h). The plasma concentration of cotinin e has been used as an index of tobacco smoke exposure. Cotinine possib ly increases the turnover rate of platelet-activating factor (PAF) bec ause it is a potent activator of PAF hydrolase, and it may play a sign ificant role in tobacco-induced arterial thrombosis. Therefore, we stu died the distribution and retention of nicotine as it was metabolized to cotinine in the rat. Nicotine (1 mg/kg, 5 mu Ci/kg) was administere d into the femoral vein of male Sprague-Dawley rats under nembutal ane sthesia. At different times (5-60 min) after nicotine administration, nicotine and its metabolite, cotinine, were determined by HPLC in plas ma, liver, kidney, heart and brain. Within 5-10 min after administrati on, nicotine concentrations reached peak values in plasma (2,160 pmol/ ml) and the organs analyzed. The plasma level of nicotine decreased by 50% within 20 min (half-time) after its intravenous administration. T he half-time of nicotine in the brain was about 50 min. The half-times of nicotine for the other organs were about 20-25 min. The major meta bolite, cotinine, accumulated in plasma, and by about 30 min the conce ntrations of nicotine and cotinine in plasma were about equal (890-1,0 00 pmol/ml). While cotinine accumulated in plasma, nicotine was elimin ated by the kidney. While the nicotine concentrations decreased with t ime in all organs, cotinine concentrations remained constant. These ob servations indicate that nicotine is renally eliminated or metabolized to cotinine while cotinine exhibits a long retention time and accumul ates in plasma. This plasma accumulation may contribute to activation of PAF turnover rate and to thrombosis.