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Research ArticleArticle

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Pramod Upadhyaya, Cheryl L. Zimmerman and Stephen S. Hecht
Drug Metabolism and Disposition October 2002, 30 (10) 1115-1122; DOI: https://doi.org/10.1124/dmd.30.10.1115
Pramod Upadhyaya
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Cheryl L. Zimmerman
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Stephen S. Hecht
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Abstract

N′-Nitrosonornicotine (NNN) is present in significant quantities in tobacco and tobacco smoke and is believed to play an important role as a cause of cancer in people who use tobacco products. Biomarkers of NNN uptake in humans such as urinary metabolites would be useful for assessing cancer risk. Previous studies, carried out almost exclusively in rodents, have characterized urinary metabolites of NNN, but none of these would be suitable as a biomarkers of NNN uptake in humans. Therefore, we studied NNN metabolism in the patas monkey. Monkeys were treated intravenously with [5-3H]NNN, which has tritium in the pyridine ring. Blood and urine samples were collected at timed intervals. Six urinary metabolites were observed by high-performance liquid chromatography (HPLC) and were identified by their spectral properties and/or comparison to appropriate standards as follows: metabolite (% of radioactivity eluting from HPLC ± S.D.,n = 3 monkeys); 4-hydroxy-4-(3-pyridyl)butyric acid (43.8 ± 4.0); 4-oxo-4-(3-pyridyl) butyric acid (2.7 ± 0.66); norcotinine (13.1 ± 2.7); norcotinine-1N-oxide (16.5 ± 1.3); 3′-hydroxynorcotinine (16.9 ± 2.0); 3′-(O-β-d-glucopyranuronosyl)hydroxynorcotinine (5.4 ± 1.0); and unchanged NNN (0.63 ± 0.15). The two major metabolites in serum were 4-hydroxy-4-(3-pyridyl)butyric acid and norcotinine. NNN was rapidly metabolized to 4-hydroxy-4-(3-pyridyl)butyric acid, whereas the formation of norcotinine and 3′-hydroxynorcotinine were somewhat delayed. The results of this study demonstrate substantial differences between NNN metabolism in the rodent and patas monkey. Metabolism of NNN to norcotinine and its derivatives was far more prevalent in the patas monkey than in the rat. 3′-Hydroxynorcotinine and itsO-glucuronide may be formed from NNN via α-oximinonornicotine or isomyosmine. There was no evidence that it was formed via norcotinine, although this pathway could not be excluded. 3′-Hydroxynorcotinine could potentially be a biomarker of NNN uptake in humans.

Footnotes

  • This study was supported by Grants CA-44377 and CA-81301 from the National Cancer Institute

  • Abbreviations used are::
    NNN
    N′-nitrosonornicotine
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    NNN-N-oxide
    N′-nitrosonornicotine-1-N-oxide
    keto alcohol
    4-hydroxy-1-(3-pyridyl)-1-butanone
    keto acid
    4-oxo-4-(3-pyridyl)butyric acid
    diol
    4-hydroxy-4-(3-pyridyl)-1-butanol
    lactol
    2-hydroxy-5-(3-pyridyl)tetrahydrofuran
    hydroxy acid
    4-hydroxy-4-(3-pyridyl)butyric acid
    lactone
    5-(3-pyridyl)tetrahydrofuran-2-one
    HPLC
    high-performance liquid chromatography
    MS
    mass spectometry
    GC
    gas chromatography
    CI
    chemical ionization
    MS/MS
    tandem mass spectometry
    PBS
    phosphate-buffered saline
    AUC
    area under the curve
    • Received February 2, 2002.
    • Accepted July 1, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Pramod Upadhyaya, Cheryl L. Zimmerman and Stephen S. Hecht
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1115-1122; DOI: https://doi.org/10.1124/dmd.30.10.1115

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Research ArticleArticle

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Pramod Upadhyaya, Cheryl L. Zimmerman and Stephen S. Hecht
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1115-1122; DOI: https://doi.org/10.1124/dmd.30.10.1115
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