Abstract
Several behavioral studies report that adolescent rats display a preference for nicotine compared with 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 s.c. (1.0 mg base/kg) or i.v. (0.2 mg base/kg) injection to early adolescent (EA; postnatal day 25) and adult (AD; postnatal day 71) 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 liquid chromatography–tandem mass spectrometry. Following s.c. 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 i.v. 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 the EA cohort compared with the AD cohort. 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 with adults, suggesting that this should be considered when interpreting animal model data.
Footnotes
- Received April 22, 2014.
- Accepted June 30, 2014.
This study was conducted with the support of an Endowed Chair in Addictions (to R.F.T.) and the Canadian Institute of Health Research [Grant MOP97751], National Institutes of Health [Grant U01-DA020830], Canada Foundation for Innovation [Grants 20289 and 16014], Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health, and Ontario Ministry of Research and Innovation.
R.F.T. has participated in one-day consulting meetings for Novartis and McNeil.
Parts of this work were previously presented at the following meeting: Craig E, Khokhar JY, Zhao B, Novalen M, Miksys SM, and Tyndale RF (2013) Altered nicotine pharmacokinetics in adolescent versus adult rats impacts the interpretation of animal model data. Society for Research on Nicotine and Tobacco Annual Meeting; 2013 Mar 13–16; Boston, MA.
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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