title: Nicotine pharmacokinetics in rats is altered as a function of age, impacting the interpretation of animal model data.
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.
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.).
authors: Evelyn L
authors: EL
authors: Craig
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.).
authors: Bin
authors: B
authors: Zhao
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.).
authors: Jason Z
authors: JZ
authors: Cui
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.).
authors: Maria
authors: M
authors: Novalen
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.).
authors: Sharon
authors: S
authors: Miksys
authors: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada (E.L.C., B.Z., M.N., S.M., R.F.T.) and Child & Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.Z.C.) r.tyndale@utoronto.ca.
authors: Rachel F
authors: RF
authors: Tyndale
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D003367:Cotinine / Q000031:analogs & derivatives / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009538:Nicotine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D010949:Plasma / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003497:Cyclic N-Oxides; C066333:norcotinine; C001381:hydroxycotinine; C024270:nicotine 1-N-oxide; D009538:Nicotine; C005311:nornicotine; D003367:Cotinine