RT Journal Article
SR Electronic
T1 Nicotine Pharmacokinetics in Rats is altered as a function of Age, impacting the Interpretation of Animal Model Data
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.114.058719
DO 10.1124/dmd.114.058719
A1 Evelyn L. Craig
A1 Bin Zhao
A1 Jason Z. Cui
A1 Maria Novalen
A1 Sharon Miksys
A1 Rachel F. Tyndale
YR 2014
UL http://dmd.aspetjournals.org/content/early/2014/06/30/dmd.114.058719.abstract
AB 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.