Nicotine pharmacokinetics in rats is altered as a function of age, impacting the interpretation of animal model data
Open accessAbstract
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.
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Nicotine is metabolized faster in rodents during pre-adolescence (P23-25) than in adults, producing lower blood levels, but no pharmacokinetic differences are seen during the adolescent period starting at P28.
“Although nicotine is more rapidly metabolized in rodents during pre-adolescence (P23–25) than in adults, leading to lower blood levels, no pharmacokinetic differences have been seen during the adolescent period starting at P28 (Portugal et al., 2012; Ahsan et al., 2014; Craig et al., 2014; Arany et al., 2017).”
From Unique, long-term effects of nicotine on adolescent brain. (2020) · cites this paper as Craig et al., 2014
The Abstract and Results report lower plasma nicotine levels and faster nicotine clearance in early-adolescent rats at postnatal day 25 than in adults. The Discussion does not support the more specific claim that faster metabolism caused the lower levels; it points primarily to clearance and distribution and does not find faster conversion to cotinine. The paper compares day-25 rats with adults, so it does not establish that pharmacokinetic differences disappear starting at day 28. Page numbers were unavailable in our copy. (LLM, conf=0.88)
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Unique, long-term effects of nicotine on adolescent brain.
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- Authors
- Craig, E. L., Zhao, B., Cui, J. Z., Novalen, M., Miksys, S., & Tyndale, R. F.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 42
- Issue
- 9
- Pages
- 1447-1455
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC4152873
- OpenAlex
- W2119204312
- Cited by
- 59
- References
- 61
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 3
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP97751)
- National Institute on Drug Abuse (U01DA020830)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- nicotine pharmacokinetics, age differences, adolescent rats, nicotine metabolism, cotinine, nornicotine, trans-3'-hydroxycotinine, brain-to-plasma ratio, volume of distribution, plasma clearance, nicotine preference
- MeSH terms
- Animals, Brain, Cotinine, Cyclic N-Oxides, Male, Nicotine, Plasma, Rats, Wistar, Area Under Curve, Models, Animal, Rats
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