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Research ArticleArticle

Metabolites of Nicotine in Rat Brain After Peripheral Nicotine Administration

Cotinine, Nornicotine, and Norcotinine

Peter A. Crooks, Min Li and Linda P. Dwoskin
Drug Metabolism and Disposition January 1997, 25 (1) 47-54;
Peter A. Crooks
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Min Li
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Linda P. Dwoskin
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Cotinine, Nornicotine, and Norcotinine

Abstract

The time course of nicotine metabolite appearance in brain from 5 min–18 hr after subcutaneous administration ofS-(−)-[3H-N-methyl]nicotine was determined. Results demonstrated that metabolite appearance in brain was greatest at 4 hr postadministration, whereas levels of nicotine were greatly diminished at this time point. For determination ofN-demethylated metabolites, (±)-[2′-14C]nicotine was administered subcutaneously to rats, and the presence of nicotine and nicotine metabolites in brain supernatant was determined 4 hr postadministration. Using high-performance liquid radiochromatographic analysis, nicotine and three nicotine metabolites (cotinine, nornicotine, and norcotinine) were identified in brain, together with a fourth minor, unidentified metabolite. After subcutaneous administration ofS-(−)-[G-3H]cotinine, significant amounts of cotinine were found in brain over an 18-hr postadministration period; however, no cotinine metabolites were detected. Therefore, cotinine is able to pass the blood-brain barrier and access the central nervous system, but is not biotransformed in brain. Thus, this is the first report of norcotinine as a central nervous system nicotine metabolite. Data indicate that norcotinine detected in brain after peripheral nicotine administration most likely originates from 5′-C-oxidation of brain nornicotine, rather than from N-demethylation of cotinine, as occurs peripherally. Because peripheral biotransformation of nicotine to nornicotine is a minor pathway, the relatively high levels of nornicotine found in brain after peripheral nicotine administration suggest that nornicotine is formed viaoxidative N-demethylation of nicotine locally in brain. Nornicotine is pharmacologically active; thus, its presence in brain after peripheral nicotine administration indicates that nornicotine may contribute to the neuropharmacological effects of nicotine and tobacco use.

Footnotes

  • Send reprint requests to: Dr. Peter A. Crooks, College of Pharmacy, University of Kentucky, Rose Street, Lexington, KY 40536-0082.

  • This work was supported by the Tobacco and Health Research Institute (Lexington, KT).

  • ↵2 L. H. Teng et al., submitted for publication, 1996.

  • Abbreviations used are::
    iv
    intravenous, HPLRC, high-performance liquid radiochromatography
    sc
    subcutaneous
    CNS
    central nervous system
    • Received March 21, 1996.
    • Accepted October 1, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Metabolites of Nicotine in Rat Brain After Peripheral Nicotine Administration

Peter A. Crooks, Min Li and Linda P. Dwoskin
Drug Metabolism and Disposition January 1, 1997, 25 (1) 47-54;

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Research ArticleArticle

Metabolites of Nicotine in Rat Brain After Peripheral Nicotine Administration

Peter A. Crooks, Min Li and Linda P. Dwoskin
Drug Metabolism and Disposition January 1, 1997, 25 (1) 47-54;
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