Cotinine
{{short description|Alkaloid found in tobacco}}
{{Distinguish|cotinin}}
{{Use dmy dates|date=February 2021}}
{{Drugbox
| verifiedrevid = 414086996
| IUPAC_name = (5S)-1-methyl-5-(3-pyridyl)pyrrolidin-2-one
| image = Cotinine2DACS.svg
| tradename =
| legal_status = Rx-only
| routes_of_administration = Oral, Smoked, Insufflation
| elimination_half-life = 20 hours
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 486-56-6
| ATC_prefix = none
| PubChem = 854019
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 746405
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = K5161X06LL
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 578211
| C=10 | H=12 | N=2 | O=1
| smiles = O=C2N(C)[C@H](c1cnccc1)CC2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UIKROCXWUNQSPJ-VIFPVBQESA-N
| density =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| specific_rotation =
}}
Cotinine is an alkaloid found in tobacco{{cite journal | vauthors = Laszlo C, Kaminski K, Guan H, Fatarova M, Wei J, Bergounioux A, Schlage WK, Schorderet-Weber S, Guy PA, Ivanov NV, Lamottke K, Hoeng J | title = Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two Nicotiana Species | journal = Molecules | volume = 27 | issue = 22 | page = 8105 | date = November 2022 | pmid = 36432206 | pmc = 9694777 | doi = 10.3390/molecules27228105 | doi-access = free }} and is also the predominant metabolite of nicotine,{{Cite book| vauthors = Triggle DJ | title = Dictionary of Pharmacological Agents | publisher = Chapman & Hall/CRC | location = Boca Raton | year = 1996 | isbn = 978-0-412-46630-4 | url = https://books.google.com/books?id=DeX7jgInYFMC&q=scotine%20cotinine&pg=PA522}}{{cite journal | vauthors = Dwoskin LP, Teng L, Buxton ST, Crooks PA | title = (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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 288 | issue = 3 | pages = 905–911 | date = March 1999 | pmid = 10027825 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10027825 }} typically used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, post-traumatic stress disorder (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.
Similarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison.{{cite journal | vauthors = Anderson DJ, Arneric SP | title = Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain | journal = European Journal of Pharmacology | volume = 253 | issue = 3 | pages = 261–267 | date = March 1994 | pmid = 8200419 | doi = 10.1016/0014-2999(94)90200-3 }}{{cite journal | vauthors = Briggs CA, McKenna DG | title = Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists | journal = Neuropharmacology | volume = 37 | issue = 9 | pages = 1095–1102 | date = September 1998 | pmid = 9833639 | doi = 10.1016/S0028-3908(98)00110-5 | s2cid = 45834866 }}{{cite journal | vauthors = Buccafusco JJ, Shuster LC, Terry AV | title = Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine | journal = Neuroscience Letters | volume = 413 | issue = 1 | pages = 68–71 | date = February 2007 | pmid = 17157984 | doi = 10.1016/j.neulet.2006.11.028 | s2cid = 6859655 }} It has demonstrated nootropic and antipsychotic-like effects in animal models.{{cite journal | vauthors = Buccafusco JJ, Terry AV | title = A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists | journal = Biochemical Pharmacology | volume = 78 | issue = 7 | pages = 852–862 | date = October 2009 | pmid = 19577545 | pmc = 2728139 | doi = 10.1016/j.bcp.2009.06.102 }}{{cite journal | vauthors = Buccafusco JJ, Beach JW, Terry AV | title = Desensitization of nicotinic acetylcholine receptors as a strategy for drug development | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 328 | issue = 2 | pages = 364–370 | date = February 2009 | pmid = 19023041 | pmc = 2682277 | doi = 10.1124/jpet.108.145292 }} Cotinine treatment has also been shown to reduce depression, anxiety, and fear-related behavior as well as memory impairment in animal models of depression, post-traumatic stress disorder, and Alzheimer's disease.{{cite journal | vauthors = Grizzell JA, Echeverria V | title = New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine | journal = Neurochemical Research | volume = 40 | issue = 10 | pages = 2032–2046 | date = October 2015 | pmid = 24970109 | doi = 10.1007/s11064-014-1359-2 | s2cid = 9393548 }} Nonetheless, treatment with cotinine in humans was reported to have no significant physiologic, subjective, or performance effects in one study,{{cite journal | vauthors = Hatsukami DK, Grillo M, Pentel PR, Oncken C, Bliss R | title = Safety of cotinine in humans: physiologic, subjective, and cognitive effects | journal = Pharmacology, Biochemistry, and Behavior | volume = 57 | issue = 4 | pages = 643–650 | date = August 1997 | pmid = 9258989 | doi = 10.1016/s0091-3057(97)80001-9 | s2cid = 13460499 }} though others suggest that this may not be the case.{{cite journal | vauthors = Moran VE | title = Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption | journal = Frontiers in Pharmacology | volume = 3 | pages = 173 | date = Oct 2012 | pmid = 23087643 | pmc = 3467453 | doi = 10.3389/fphar.2012.00173 | doi-access = free }}
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.{{cite journal | vauthors = Crooks PA, Dwoskin LP | title = Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking | journal = Biochemical Pharmacology | volume = 54 | issue = 7 | pages = 743–753 | date = October 1997 | pmid = 9353128 | doi = 10.1016/s0006-2952(97)00117-2 }}
Pharmacology
A few studies indicate that the affinity for cotinine to the nicotinic acetylcholine receptors (nAChRs) is about 100 times lower than nicotine's. Some work suggests that cotinine may be a positive allosteric modulator of α7 nAChRs.{{cite journal | vauthors = Young GT, Zwart R, Walker AS, Sher E, Millar NS | title = Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 38 | pages = 14686–14691 | date = September 2008 | pmid = 18791069 | doi = 10.1073/pnas.0804372105 | doi-access = free | pmc = 2535569 | bibcode = 2008PNAS..10514686Y }} If this is true, cotinine would facilitate endogenous neurotransmission without directly stimulating nAChRs.
=Pharmacokinetics=
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.{{cite journal | vauthors = Florescu A, Ferrence R, Einarson T, Selby P, Soldin O, Koren G | title = Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology | journal = Therapeutic Drug Monitoring | volume = 31 | issue = 1 | pages = 14–30 | date = February 2009 | pmid = 19125149 | pmc = 3644554 | doi = 10.1097/FTD.0b013e3181957a3b }} People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine.{{Cite web| vauthors = Ham B |title=Signs of smoking linger longer in menthol smokers |work=Center for the Advancement of Health |publisher=Science Blog |date=December 2002 |url=http://www.scienceblog.com/community/older/2002/G/20021531.html |access-date=17 March 2010 |archive-url=https://web.archive.org/web/20100626005027/http://www.scienceblog.com/community/older/2002/G/20021531.html |archive-date=26 June 2010 |url-status=dead }} African American smokers generally have higher plasma cotinine levels than Caucasian smokers.{{cite journal | vauthors = Wagenknecht LE, Cutter GR, Haley NJ, Sidney S, Manolio TA, Hughes GH, Jacobs DR | title = Racial differences in serum cotinine levels among smokers in the Coronary Artery Risk Development in (Young) Adults study | journal = American Journal of Public Health | volume = 80 | issue = 9 | pages = 1053–1056 | date = September 1990 | pmid = 2382740 | pmc = 1404871 | doi = 10.2105/ajph.80.9.1053 }} Males generally have higher plasma cotinine levels than females.{{cite journal | vauthors = Gan WQ, Cohen SB, Man SF, Sin DD | title = Sex-related differences in serum cotinine concentrations in daily cigarette smokers | journal = Nicotine & Tobacco Research | volume = 10 | issue = 8 | pages = 1293–1300 | date = August 2008 | pmid = 18686176 | doi = 10.1080/14622200802239132 }} These systematic differences in cotinine levels were attributed to variation in CYP2A6 activity.{{cite journal | vauthors = Zhu AZ, Renner CC, Hatsukami DK, Swan GE, Lerman C, Benowitz NL, Tyndale RF | title = The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 22 | issue = 4 | pages = 708–718 | date = April 2013 | pmid = 23371292 | pmc = 3617060 | doi = 10.1158/1055-9965.EPI-12-1234-T }} 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. 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.
=Detection in body fluids=
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.Avila-Tang, Erika et al (September 2012). "Assessing secondhand smoke using biological markers" - Nicotine and metabolites [http://tobaccocontrol.bmj.com/content/early/2012/09/01/tobaccocontrol-2011-050298.full]. Retrieved 10 June 2013
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.{{cite journal | vauthors = Jarvis MJ, Fidler J, Mindell J, Feyerabend C, West R | title = Assessing smoking status in children, adolescents and adults: cotinine cut-points revisited | journal = Addiction | volume = 103 | issue = 9 | pages = 1553–1561 | date = September 2008 | pmid = 18783507 | doi = 10.1111/j.1360-0443.2008.02297.x | url = https://discovery.ucl.ac.uk/id/eprint/6751/ }} 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.{{cite web| vauthors = Hewitt D |title=Reasons for False Positives for Nicotine on a Blood Test|url=http://www.livestrong.com/article/26557-reasons-false-positives-nicotine-blood/|publisher=LiveStrong.com|access-date=21 October 2011}} 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.{{cite web | vauthors = McNeil A, Brose LS, Calder R, Hitchman SC, Hajek P, McRobbie H |title=E-cigarettes: an evidence update. A report commissioned by Public Health England |url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/454516/Ecigarettes_an_evidence_update_A_report_commissioned_by_Public_Health_England.pdf|website=Gov.uk|publisher=Public Health England |pages=70–75|access-date=20 August 2015|location=UK|date=2015}}
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.{{cite journal | vauthors = Tsai J, Homa DM, Gentzke AS, Mahoney M, Sharapova SR, Sosnoff CS, Caron KT, Wang L, Melstrom PC, Trivers KF | display-authors = 6 | title = Exposure to Secondhand Smoke Among Nonsmokers - United States, 1988-2014 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 67 | issue = 48 | pages = 1342–1346 | date = December 2018 | pmid = 30521502 | pmc = 6329485 | doi = 10.15585/mmwr.mm6748a3 | doi-access = free }} 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
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{{Nicotinic acetylcholine receptor modulators}}
Category:Alkaloids found in Nicotiana