Effect of dose on the pharmacokinetics of intravenous nicotine in the rat.
The pharmacokinetics of [methyl-14C]nicotine were evaluated in male Fischer-344 rats following the iv injection of 0.08-, 0.4-, or 0.8-mg/kg doses. Independent of dose, the concentration of nicotine declined biexponentially with a mean half-life ranging from 0.92 to 1.10 hr. However, the total plasma clearance of nicotine increased (p less than 0.05) from a mean value of 2.53 liter/hr-kg at the 0.08 mg/kg dose to mean values of 3.88 and 4.04 at the 0.4- and 0.8-mg/kg doses, respectively. There were no dose-related differences in the half-life of formation of the major metabolite, cotinine (range 0.33-0.46 hr) or the half-life of its elimination (range 5.39-6.63 hr). However, the areas under the cotinine plasma concentration-time curves did not increase proportionately with the dose of nicotine, indicating that the dose-related increase in the total plasma clearance of nicotine is not due to an increase in its biotransformation to cotinine. Similar conclusions were obtained with regard to the disposition kinetics of other polar metabolites of nicotine. The urinary excretions of nicotine and its metabolites were dose-independent.
Effect of dose on the pharmacokinetics of intravenous nicotine in the rat. The pharmacokinetics of [methyl-14C]nicotine were evaluated in male Fischer-344 rats following the iv injection of 0.08-, 0.4-, or 0.8-mg/kg doses. Independent of dose, the concentration of nicotine declined biexponentially with a mean half-life ranging from 0.92 to 1.10 hr. However, the total plasma clearance of nicotine increased (p less than 0.05) from a mean value of 2.53 liter/hr-kg at the 0.08 mg/kg dose to mean values of 3.88 and 4.04 at the 0.4- and 0.8-mg/kg doses, respectively. There were no dose-related differences in the half-life of formation of the major metabolite, cotinine (range 0.33-0.46 hr) or the half-life of its elimination (range 5.39-6.63 hr). However, the areas under the cotinine plasma concentration-time curves did not increase proportionately with the dose of nicotine, indicating that the dose-related increase in the total plasma clearance of nicotine is not due to an increase in its biotransformation to cotinine. Similar conclusions were obtained with regard to the disposition kinetics of other polar metabolites of nicotine. The urinary excretions of nicotine and its metabolites were dose-independent.