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DoroWolf/沙盒/可替寧
臨床資料
給藥途徑Oral, Smoked, Insufflation
ATC碼
  • 未分配
法律規範狀態
法律規範
  • 處方藥（℞-only）
藥物動力學數據
生物半衰期20 hours
識別資訊
  • (5S)-1-methyl-5-(3-pyridyl)pyrrolidin-2-one
CAS號486-56-6  checkY
PubChem CID
ChemSpider
UNII
ChEMBL
化學資訊
化學式C10H12N2O
摩爾質量176.22 g·mol−1
3D模型（JSmol（英語：JSmol））
  • O=C2N(C)[C@H](c1cnccc1)CC2
  • InChI=1S/C10H12N2O/c1-12-9(4-5-10(12)13)8-3-2-6-11-7-8/h2-3,6-7,9H,4-5H2,1H3/t9-/m0/s1 checkY
  • Key:UIKROCXWUNQSPJ-VIFPVBQESA-N checkY

Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine.[1][2] An anagram of the word "nicotine", it 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]

Pharmacology

編輯

A few studies indicate that the affinity for cotinine to the nicotinic acetylcholine receptors (nAChRs) is about 100 times lower than nicotine's.[10] Some work suggests that cotinine may be a positive allosteric modulator of α7 nAChRs.[12][10] If this is true, cotinine would facilitate endogenous neurotransmission without directly stimulating nAChRs.

Pharmacokinetics

編輯

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.[13] People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine.[14] African American smokers generally have higher plasma cotinine levels than Caucasian smokers.[15] Males generally have higher plasma cotinine levels than females.[16] These systematic differences in cotinine levels were attributed to variation in CYP2A6 activity.[17] 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.[17] Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genetic variation, cotinine accumulates in individuals with slower CYP2A6 activity, resulting in substantial differences in cotinine levels for a given tobacco exposure.[17]

Detection in body fluids

編輯

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]

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.[19] 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).

However, tobacco users attempting to quit with the help of nicotine replacement therapies (i.e., gum, lozenge, patch, inhaler, and nasal spray) will also test positive for cotinine, since all common NRT therapies contain nicotine that is metabolized in the same way. Therefore, the presence of cotinine is not a conclusive indication of tobacco use.[20] Cotinine levels can be used in research to explore the question of the amount of nicotine delivered to the user of e-cigarettes, where laboratory smoking machines have many problems replicating real-life conditions.[21]

Serum cotinine concentration has been used for decades in US population surveys of the Centers for Disease Control and Prevention to monitor tobacco use, to monitor levels and trends in exposure to environmental tobacco smoke, and to study the relationship between tobacco smoke and chronic health conditions.[22] An estimated one in four nonsmokers (approximately 58 million persons) were exposed to secondhand smoke during 2013-2014. Nearly 40% of children aged 3–11 years were exposed as were 50% of non-Hispanic blacks.

References

編輯
  1. ^ 1.0 1.1 David J. Triggle. Dictionary of Pharmacological Agents. Boca Raton: Chapman & Hall/CRC. 1996. ISBN 978-0-412-46630-4. 
  2. ^ 2.0 2.1 Dwoskin LP, Teng L, Buxton ST, Crooks PA. (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. March 1999, 288 (3): 905–11. PMID 10027825. 
  3. ^ Anderson DJ, Arneric SP. Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain. European Journal of Pharmacology. March 1994, 253 (3): 261–7. PMID 8200419. doi:10.1016/0014-2999(94)90200-3. 
  4. ^ Briggs CA, McKenna DG. Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists. Neuropharmacology. September 1998, 37 (9): 1095–102. PMID 9833639. S2CID 45834866. doi:10.1016/S0028-3908(98)00110-5. 
  5. ^ Buccafusco JJ, Shuster LC, Terry AV. Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine. Neuroscience Letters. February 2007, 413 (1): 68–71. PMID 17157984. S2CID 6859655. doi:10.1016/j.neulet.2006.11.028. 
  6. ^ Buccafusco JJ, Terry AV. A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists. Biochemical Pharmacology. October 2009, 78 (7): 852–62. PMC 2728139  . PMID 19577545. doi:10.1016/j.bcp.2009.06.102. 
  7. ^ Buccafusco JJ, Beach JW, Terry AV. Desensitization of nicotinic acetylcholine receptors as a strategy for drug development. The Journal of Pharmacology and Experimental Therapeutics. February 2009, 328 (2): 364–70. PMC 2682277  . PMID 19023041. doi:10.1124/jpet.108.145292. 
  8. ^ 8.0 8.1 Grizzell, JA; Echeverria, V. New insights into the mechanisms of action of cotinine and its distinctive effects from nicotine. Neurochemical Research. Jun 2014, 40 (10): 2032–46. PMID 24970109. S2CID 9393548. doi:10.1007/s11064-014-1359-2. 
  9. ^ Hatsukami, DK; Grillo, M; Pentel, PR; Oncken, C; Bliss, R. Safety of cotinine in humans: physiologic, subjective, and cognitive effects.. Pharmacology Biochemistry and Behavior. Aug 1997, 57 (4): 643–50. PMID 9258989. S2CID 13460499. doi:10.1016/s0091-3057(97)80001-9. 
  10. ^ 10.0 10.1 10.2 Moran, VE. Cotinine: Beyond that expected, more than a biomarker of tobacco consumption. Front Pharmacol. Oct 2012, 3: 173. PMC 3467453  . PMID 23087643. doi:10.3389/fphar.2012.00173  . 
  11. ^ Crooks, PA; Dwoskin, LP. Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking. Biochemical Pharmacology. Oct 1997, 54 (7): 743–53. PMID 9353128. doi:10.1016/s0006-2952(97)00117-2. 
  12. ^ Young, Gareth T.; Zwart, Ruud; Walker, Alison S.; Sher, Emanuele; Millar, Neil S. Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proceedings of the National Academy of Sciences. 23 September 2008, 105 (38): 14686–14691. doi:10.1073/pnas.0804372105  . 
  13. ^ Florescu A, Ferrence R, Einarson T, Selby P, Soldin O, Koren G. Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology. Therapeutic Drug Monitoring. February 2009, 31 (1): 14–30. PMC 3644554  . PMID 19125149. doi:10.1097/FTD.0b013e3181957a3b. 
  14. ^ Ham, Becky. Signs of smoking linger longer in menthol smokers. Center for the Advancement of Health. Science Blog. December 2002 [17 March 2010]. （原始內容存檔於26 June 2010）. 
  15. ^ Wagenknecht, LE; Cutter, GR; Haley, NJ; Sidney, S; Manolio, TA; Hughes, GH; Jacobs, DR. Racial differences in serum cotinine levels among smokers in the Coronary Artery Risk Development in (Young) Adults study.. American Journal of Public Health. Sep 1990, 80 (9): 1053–6. PMC 1404871  . PMID 2382740. doi:10.2105/ajph.80.9.1053. 
  16. ^ Gan, WQ; Cohen, SB; Man, SF; Sin, DD. Sex-related differences in serum cotinine concentrations in daily cigarette smokers.. Nicotine & Tobacco Research. Aug 2008, 10 (8): 1293–300. PMID 18686176. doi:10.1080/14622200802239132. 
  17. ^ 17.0 17.1 17.2 Zhu, AZ; Renner, CC; Hatsukami, DK; Swan, GE; Lerman, C; Benowitz, NL; Tyndale, RF. 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. Apr 2013, 22 (4): 708–18. PMC 3617060  . PMID 23371292. doi:10.1158/1055-9965.EPI-12-1234-T. 
  18. ^ Avila-Tang, Erika et al (September 2012). "Assessing secondhand smoke using biological markers" - Nicotine and metabolites [1]. Retrieved 10 June 2013
  19. ^ Jarvis; et al. Assessing smoking status in children, adolescents and adults: cotinine cut-points revisited (PDF). Addiction. 2008, 103 (9): 1553–61. PMID 18783507. doi:10.1111/j.1360-0443.2008.02297.x. 
  20. ^ Hewitt, Doug. Reasons for False Positives for Nicotine on a Blood Test. LiveStrong.com. [21 October 2011]. 
  21. ^ McNeill, A; Brose, LS; Calder, R; Hitchman, SC; Hajek, P; McRobbie, H. E-cigarettes: an evidence update. A report commissioned by Public Health England (PDF). Gov.uk. UK: Public Health England: 70–75. 2015 [20 August 2015]. 
  22. ^ Tsai, James; Homa, David M.; Gentzke, Andrea S.; Mahoney, Margaret; Sharapova, Saida R.; Sosnoff, Connie S.; Caron, Kevin T.; Wang, Lanqing; Melstrom, Paul C.; Trivers, Katrina F. Exposure to Secondhand Smoke Among Nonsmokers – United States, 1988–2014. MMWR. Morbidity and Mortality Weekly Report. 7 December 2018, 67 (48): 1342–1346. PMC 6329485  . PMID 30521502. doi:10.15585/mmwr.mm6748a3  . 

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