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 ofS(−)-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′-14C]-(±)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.
Footnotes
-
Send reprint requests to: Dr. Peter A. Crooks, College of Pharmacy, University of Kentucky, Rose Street, Lexington, Kentucky: 40536-0082; E-mail: pcrooks{at}pop.uky.edu
-
This work was supported in part by National Institute of Drug Abuse Grants DA08656 and DA00399, and by the Tobacco and Health Institute, Lexington, Kentucky.
- Abbreviations used are::
- HPLRC
- high pressure liquid radiochromatography
- GC
- gas chromatography
- GC-MS
- gas chromatography-mass spectrometry
- CNS
- central nervous system
- Received April 16, 1999.
- Accepted September 8, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|