Residence times and half-lives of nicotine metabolites in rat brain after acute peripheral administration of [2′-14C]nicotine
Abstract
The residence times of nicotine and its metabolites in rat brain after acute peripheral nicotine administration were determined. We hypothesize that nicotine metabolites will reach pharmacologically significant concentrations in brain. Cotinine, nornicotine, and norcotinine were structurally identified by dual label radiochemical and gas chromatography-mass spectrometric analysis as biotransformation products of nicotine present in rat brain after s. c. injection of S(-)-nicotine. Two unidentified minor metabolites were also detected in brain. The half-lives in brain of nicotine metabolites were determined after a single s.c. injection of [2'-(14)C]-(+/-)nicotine (0.8 mg/kg) and analysis of radiolabeled metabolites by high pressure-liquid radiochromatography. The brain half-lives of nicotine, cotinine, and nornicotine were 52, 333, and 166 min, respectively. Peak brain concentrations of nicotine metabolites were 300, 70, and 7 nM for cotinine, nornicotine, and norcotinine, respectively. Even with potential accumulation of cotinine in brain after chronic nicotine administration, it is likely that the brain concentration of cotinine will be insufficient to produce neuropharmacological effects resulting from activation of nicotinic receptors to induce dopamine release. Conversely, the concentration of nornicotine in brain after acute nicotine approaches the range found to be neuropharmacologically active. It is likely that nornicotine will accumulate in brain on chronic nicotine administration based on the brain half-life of this metabolite. Importantly, nornicotine is also a major alkaloidal component of tobacco. Thus, as a consequence of tobacco use, alkaloidal and metabolically formed nornicotine may reach concentrations in brain sufficient to produce pharmacological effects.
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The brain levels and brain-to-blood ratios for nicotine and varenicline matched values reported in earlier work.
“moreover, both the concentrations and the brain-to-blood ratios of nicotine and varenicline were similar to previously reported values (Ghosheh et al., 1999;Doura et al., 2008;Rollema et al., 2010).”
From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Ghosheh et al., 1999
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- Authors
- Ghosheh, O., Dwoskin, L. P., Li, W.-K., & Crooks, P. A.
- Affiliations
- University of Kentucky (US)
- ORCID
- Crooks, Peter A.
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1999-12
- Volume
- 27
- Issue
- 12
- Pages
- 1448-1455
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W1880389432
- Cited by
- 108
- References
- 37
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 10
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institutes of Health (5r01da008656-03)
- National Institute on Drug Abuse (DA-08656, DA-00399, K02DA000399)
- 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, nicotine metabolites, cotinine, nornicotine, dopamine release, tobacco alkaloids, rat brain
- MeSH terms
- Animals, Brain, Carbon Radioisotopes, Cotinine, Half-Life, Male, Gas Chromatography-Mass Spectrometry, Nicotine, Time Factors, Rats, Sprague-Dawley, Rats
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