Cotinine

Not to be confused with cotinin.
Cotinine
Systematic (IUPAC) name
(5S)-1-methyl-5-(3-pyridyl)pyrrolidin-2-one
Clinical data
Routes of
administration		 Oral, Smoked, Insufflation
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Biological half-life 20 hours
Identifiers
CAS Number 486-56-6 YesY
ATC code none
PubChem CID 854019
ChemSpider 746405 YesY
UNII K5161X06LL YesY
ChEMBL CHEMBL578211 YesY
Chemical data
Formula C10H12N2O
Molar mass 176.22 g/mol
  (verify)

Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine.[1][2] The word "cotinine" is an anagram of "nicotine". Cotinine is used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, PTSD, schizophrenia, Alzheimer's disease and Parkinson's disease. Cotinine was developed as an antidepressant as a fumaric acid salt, cotinine fumarate, to be sold under the brand name Scotine but it was never marketed.[1]

Similarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison.[2][3][4][5] It has demonstrated nootropic and antipsychotic-like effects in animal models.[6][7] Cotinine treatment has also been shown to reduce depression, anxiety, and fear-related behavior as well as memory impairment in animal models of depression, PTSD, and Alzheimer's disease.[8] Nonetheless, treatment with cotinine in humans was reported to have no significant physiologic, subjective, or performance effects in one study,[9] though others suggest that this may not be the case.[10]

Because cotinine is the main metabolite to nicotine and has been shown to be pharmacologically active, it has been suggested that some of nicotine's effects in the nervous system may be mediated by cotinine and/or complex interactions with nicotine itself.[8][11]

Measure of cotinine exposure

Cotinine has an in vivo half-life of approximately 20 hours, and is typically detectable for several days (up to one week) after the use of tobacco. The level of cotinine in the blood, saliva, and urine is proportionate to the amount of exposure to tobacco smoke, so it is a valuable indicator of tobacco smoke exposure, including secondary (passive) smoke.[12] People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine.[13] African American smokers generally have higher plasma cotinine levels than Caucasian smokers.[14] Males generally have higher plasma cotinine levels than females.[15] These systematic differences in cotinine levels were attributed to variation in CYP2A6 activity.[16] At steady state, plasma cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6.[16] Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and race (due to genetic variation), cotinine accumulates in individuals with slower CYP2A6 activity, resulting in substantial differences in cotinine levels for a given tobacco exposure.[16]

Cotinine levels <10 ng/mL are considered to be consistent with no active smoking. Values of 10 ng/mL to 100 ng/mL are associated with light smoking or moderate passive exposure, and levels above 300 ng/mL are seen in heavy smokers - more than 20 cigarettes a day. In urine, values between 11 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 500 ng/mL or more. In saliva, values between 1 ng/ml and 30 ng/ml may be associated with light smoking or passive exposure, and levels in active smokers typically reach 100 ng/ml or more.[17] Cotinine assays provide an objective quantitative measure that is more reliable than smoking histories or counting the number of cigarettes smoked per day. Cotinine also permits the measurement of exposure to second-hand smoke (passive smoking).

Drug tests can detect cotinine in the blood, urine, or saliva. Salivary cotinine concentrations are highly correlated to blood cotinine concentrations, and can detect cotinine in a low range, making it the preferable option for a less invasive method of tobacco exposure testing. Urine cotinine concentrations average four to six times higher than those in blood or saliva, making urine a more sensitive matrix to detect low-concentration exposure.[18]

However, nicotine replacement therapies (i.e., gum, lozenge, patch, inhaler, and nasal spray) used to help tobacco users quit contain nicotine. Use of nicotine replacement therapy will result in a positive test for cotinine. Therefore, the presence of cotinine is not a conclusive indication of tobacco use.[19] Cotinine levels can be used in research to explore the vexed question of the amount of nicotine delivered to the user of e-cigarettes, where laboratory smoking machines have many problems replicating real-life conditions.[20]

References

  1. 1 2 David J. Triggle (1996). Dictionary of Pharmacological Agents. Boca Raton: Chapman & Hall/CRC. ISBN 0-412-46630-9.
  2. 1 2 Dwoskin LP, Teng L, Buxton ST, Crooks PA (March 1999). "(S)-(−)-Cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [3H]dopamine release from rat striatal slices in a calcium-dependent manner". The Journal of Pharmacology and Experimental Therapeutics 288 (3): 905–11. PMID 10027825.
  3. ↑ Anderson DJ, Arneric SP (March 1994). "Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain". European Journal of Pharmacology 253 (3): 261–7. doi:10.1016/0014-2999(94)90200-3. PMID 8200419.
  4. ↑ Briggs CA, McKenna DG (September 1998). "Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists". Neuropharmacology 37 (9): 1095–102. doi:10.1016/S0028-3908(98)00110-5. PMID 9833639.
  5. ↑ Buccafusco JJ, Shuster LC, Terry AV (February 2007). "Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine". Neuroscience Letters 413 (1): 68–71. doi:10.1016/j.neulet.2006.11.028. PMID 17157984.
  6. ↑ Buccafusco JJ, Terry AV (October 2009). "A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists". Biochemical Pharmacology 78 (7): 852–62. doi:10.1016/j.bcp.2009.06.102. PMC 2728139. PMID 19577545.
  7. ↑ Buccafusco JJ, Beach JW, Terry AV (February 2009). "Desensitization of nicotinic acetylcholine receptors as a strategy for drug development". The Journal of Pharmacology and Experimental Therapeutics 328 (2): 364–70. doi:10.1124/jpet.108.145292. PMC 2682277. PMID 19023041.
  8. 1 2 Grizzell, JA; Echeverria, V (Jun 2014). "New insights into the mechanisms of action of cotinine and its distinctive effects from nicotine". Neurochemical Research 27: 2032–46. doi:10.1007/s11064-014-1359-2. PMID 24970109.
  9. ↑ Hatsukami, DK; Grillo, M; Pentel, PR; Oncken, C; Bliss, R (Aug 1997). "Safety of cotinine in humans: physiologic, subjective, and cognitive effects.". Pharmacology, Biochemistry, and Behavior 57 (4): 643–50. doi:10.1016/s0091-3057(97)80001-9. PMID 9258989.
  10. ↑ Moran, VE (Oct 2012). "Cotinine: Beyond that expected, more than a biomarker of tobacco consumption". Front Pharmacology 10 (3): 173. doi:10.3389/fphar.2012.00173. PMID 23087643.
  11. ↑ Crooks, PA; Dwoskin, LP (Oct 1997). "Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking". Biochemical Pharmacology 1 (54): 743–53. doi:10.1016/s0006-2952(97)00117-2. PMID 9353128.
  12. ↑ Florescu A, Ferrence R , Einarson T, Selby P, Soldin O, Koren G (February 2009). "Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology". Therapeutic Drug Monitoring 31 (1): 14–30. doi:10.1097/FTD.0b013e3181957a3b. PMC 3644554. PMID 19125149.
  13. ↑ Ham, Becky (December 2002). "Signs of smoking linger longer in menthol smokers". Center for the Advancement of Health. Science Blog. Archived from the original on 17 March 2010. Retrieved 17 March 2010.
  14. ↑ Wagenknecht, LE; Cutter, GR; Haley, NJ; Sidney, S; Manolio, TA; Hughes, GH; Jacobs, DR (Sep 1990). "Racial differences in serum cotinine levels among smokers in the Coronary Artery Risk Development in (Young) Adults study.". American Journal of Public Health 80 (9): 1053–6. doi:10.2105/ajph.80.9.1053. PMC 1404871. PMID 2382740.
  15. ↑ Gan, WQ; Cohen, SB; Man, SF; Sin, DD (Aug 2008). "Sex-related differences in serum cotinine concentrations in daily cigarette smokers.". Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 10 (8): 1293–300. doi:10.1080/14622200802239132. PMID 18686176.
  16. 1 2 3 Zhu, AZ; Renner, CC; Hatsukami, DK; Swan, GE; Lerman, C; Benowitz, NL; Tyndale, RF (Apr 2013). "The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.". Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22 (4): 708–18. doi:10.1158/1055-9965.EPI-12-1234-T. PMC 3617060. PMID 23371292.
  17. ↑ Jarvis; et al. (2008). "Assessing smoking status in children, adolescents and adults: cotinine cut-points revisited". Addiction 103 (9): 1553–61. doi:10.1111/j.1360-0443.2008.02297.x.
  18. ↑ Avila-Tang, Erika et al (September 2012). "Assessing secondhand smoke using biological markers" - Nicotine and metabolites . Retrieved 10 June 2013
  19. ↑ Hewitt, Doug. "Reasons for False Positives for Nicotine on a Blood Test". LiveStrong.com. Retrieved 21 October 2011.
  20. ↑ McNeill, A, SC (2015). "E - cigarettes: an evidence update A report commissioned by Public Health England" (PDF). www.gov.uk. UK: Public Health England. p. 70–75. Retrieved 20 August 2015.
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