摘要：

Pharmacokinetics of Nicotine in Rats Abstract of the- presentation given by Joseph Adir, -Ph.D. to the Contractors' Conference of the Smoking and Health Program, July 17-18, 1975, Atlantic City, ldew Jersey - The pharmacokinetics of nicotinL-were evaluated following the intravenous administration-of 0.08, 0.4 and 0.8 mg/kg doses of nicotine-metlryl-14C to male Fischer-344 rats. Blood samples were drawn-at intervals for 30 hours post-administration-via a cannula chronically implanted irito the abdominal aorta and urine was collected for 48-hours. Nicotine and-its metabolites were separated by TLC and the radioactivity corresponding to nicotine, cotinine and other metabolites was determined by liquid scintillation count- ing. Nicotine and cotinine zones were identified by comparison with authentic samples and by mass spectrometry. The results s-how that irrespective of dose,nicotine disappeared rapidly from plasma while high levels of cotinine and other metabolites persisted- for 30 hours post-injection. The decline of-nicotine-concentration was biex-ponential at the various-doses studied. An average half-life (tz) of 0.26 hours for the a-phase and 0-.9b hours for the S-phase were estimated from computer-fitting of the data (N=6). Nicotine possesses a much higher volume of distribution and total body clearance in rats compared with its major metabolite, cotinine. Although cotinine is rapidly formed (t'-1 of formation of 0.46 hours), its elimination from plasma is much slower with an average t2 of 6.4 hours. Tl.e radioactivity remaining at thce origin of the TLC plates, which is probably due to-nicotine-N-oxide, was found to build up very rapidly in plasma (tz of 0.05 hours) but declines at a very slow rate corresponding to a mean t2 of 22.8 hours. - These results indicate that inspite of the rapid disappearance of nicotine from the rat plasma, significant levels of its metabolites persist for long time- post-administration of nicotine. The implication of this finding on the-toxicity of nicotine remains to be delineated. It is also clear that within the doses studied, the pharmacokinetics of nicotine in rats after acute administration appear to be dose independent. This is evident by the linear increase in maximum plasma-concentration of cotinine and nicotine-N-oxide, the similarity in the pharmacokinetic parameters of formation and elimination of these-metabolites, the constancy of the volume of distribution of nicotine and the similarity of the area-under-the-plasma curves of nicotine and its metabolites-at the various doses studied. The occurrence of dose-related changes in the pharmacokinetics of nicotine after chronic administration is yet to be elucidated. c

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