Effect of ethanol pretreatment on the pharmacokinetics of nicotine in rats

Abstract

The pharmacokinetics of nicotine was compared in male Fischer-344 rats pretreated with an ethanol or a sucrose solution for 12.5 days. The animals received either ethanol at doses of 4 g/kg/day for 7 days followed by 8 g/kg/day for 5.5 days or daily doses of an isocaloric-isovolumetric sucrose solution for 12.5 days by gastric intubation. On the fourteenth day, a 0.4 mg/kg dose of [methyl-14C]nicotine was injected i.v. to both groups, and blood samples were collected at timed intervals for 30 hr. Nicotinine and its metabolites in plasma were separated by thin-layer chromatography and quantitated by liquid scintillation counting. The plasma levels of total radioactivity, nicotine, cotinine and other polar metabolites were significantly lower in the ethanol as compared to the sucrose-treated rats. Ethanol pretreatment produced no changes in the hybrid rate constants describing the biphasic decline of plasma nicotine concentration but its apparent volume of distribution and total plasma clearance were increased by 45% (P less than .05) suggesting that ethanol may alter the distribution of nicotine. The apparent volume of distribution of cotinine and its rate of production also were significantly increased indicating an ethanol-related induction of this major metabolite of nicotine.