Abstract
Several behavioral studies report that adolescent rats display a preference for nicotine compared to adults. However, age-related pharmacokinetic differences may confound the interpretation of these findings. Thus, differences in pharmacokinetic analyses of nicotine were investigated. Nicotine was administered via acute subcutaneous (1.0 mg base/kg) or intravenous (0.2 mg base/kg) injection to early adolescent (EA; PND25) and adult (AD; PND71) male Wistar rats. Nicotine and its primary metabolite cotinine, and additional metabolites nornicotine, nicotine-1'-N-oxide, trans-3'-hydroxycotinine and norcotinine were sampled from 10 minutes to 8 hours (plasma) and 2 to 8 hours (brain) post nicotine and analyzed by LC-MS/MS. Following subcutaneous nicotine, the EA cohort had lower levels of plasma nicotine, cotinine and nicotine-1'-N-oxide at multiple time points, resulting in a lower area under the plasma concentration-time curve (AUC) for nicotine (p<0.001), cotinine (p<0.01) and nicotine-1'-N-oxide (p<0.001). Brain levels were also lower for these compounds. In contrast, the EA cohort had higher plasma and brain AUCs (p<0.001) for the minor metabolite nornicotine. Brain to plasma ratios varied for nicotine and its metabolites, and by age. Following intravenous nicotine administration similar age-related differences were observed, and this route allowed detection of a 1.6-fold larger volume of distribution and 2-fold higher plasma clearance in EA cohort compared to AD cohort respectively. Thus, unlike in humans, there are substantial age differences in nicotine pharmacokinetics such that for a given nicotine dose, adolescent rats will have lower plasma and brain nicotine compared to adults suggesting that this should be considered when interpreting animal model data.
- The American Society for Pharmacology and Experimental Therapeutics