Editing Sertraline (section)

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright sortable" style="font-size:small;"
|+ Molecular targets of sertraline<ref name="PDSP">{{cite web | title = PDSP ''K''<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=sertraline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>
|-
! data-sort-type=number | Site !! ''K''<sub>i</sub> (nM) !! Species || References
|-
| {{abbrlink|SERT|Serotonin transporter}} || 0.15–3.3 || Human || <ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–58 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}</ref><ref name="pmid9400006">{{cite journal | vauthors = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 3 | pages = 1305–22 | date = December 1997 | doi = 10.1016/S0022-3565(24)37161-7 | pmid = 9400006 }}</ref><ref name="pmid11543737">{{cite journal | vauthors = Owens MJ, Knight DL, Nemeroff CB | title = Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine | journal = Biological Psychiatry | volume = 50 | issue = 5 | pages = 345–50 | date = September 2001 | pmid = 11543737 | doi = 10.1016/s0006-3223(01)01145-3 | s2cid = 11247427 }}</ref>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 420–925 || Human || <ref name="pmid9537821" /><ref name="pmid9400006" /><ref name="pmid11543737" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || 22–315 || Human || <ref name="pmid9537821" /><ref name="pmid9400006" /><ref name="pmid11543737" />
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 35000+ || Human || <ref name="pmid7855217">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–65 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }}</ref>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 2207 || Rat || <ref name="pmid11543737" />
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 2298 || Pig || <ref name="pmid11543737" />
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 1900 || Human ||<ref name="pmid32608144">{{cite journal |vauthors=Proudman RG, Pupo AS, Baker JG |title=The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors |journal=Pharmacol Res Perspect |volume=8 |issue=4 |pages=e00602 |date=August 2020 |pmid=32608144 |pmc=7327383 |doi=10.1002/prp2.602 |url=}}</ref>
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 3500 || Human ||<ref name="pmid32608144"/>
|-
| [[Alpha-1D adrenergic receptor|α<sub>1D</sub>]] || 2500 || Human ||<ref name="pmid32608144"/>
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>]] || 477–4100 || Human || <ref name="pmid9400006" /><ref name="pmid7855217" />
|-
| [[D2 receptor|D<sub>2</sub>]] || 10700 || Human || <ref name="pmid7855217" />
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 24000 || Human || <ref name="pmid7855217" />
|-
| {{abbrlink|mACh|Muscarinic acetylcholine receptors}} || 427–2100 || Human || <ref name="pmid11543737" /><ref name="pmid7855217" /><ref name="pmid8100134">{{cite journal | vauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson E | title = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics | journal = Biochemical Pharmacology | volume = 45 | issue = 11 | pages = 2352–4 | date = June 1993 | pmid = 8100134 | doi = 10.1016/0006-2952(93)90211-e }}</ref>
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || 32–57 || Rat || <ref name="AlbayrakHashimoto2017">{{Cite book | vauthors = Albayrak Y, Hashimoto K | series = Advances in Experimental Medicine and Biology | title = Sigma Receptors: Their Role in Disease and as Therapeutic Targets | chapter = Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders | volume = 964 | pages = 153–161 | year = 2017 | pmid = 28315270 | doi = 10.1007/978-3-319-50174-1_11 | isbn = 978-3-319-50172-7 }}</ref><ref name="pmid20373470">{{cite journal | vauthors = Hindmarch I, Hashimoto K | title = Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered | journal = Human Psychopharmacology | volume = 25 | issue = 3 | pages = 193–200 | date = April 2010 | pmid = 20373470 | doi = 10.1002/hup.1106 | s2cid = 26491662 }}</ref>
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || 5297 || Rat || <ref name="pmid20373470" />
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are ''K''<sub>i</sub> (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to or inhibits the site.
|}

Sertraline is a [[selective serotonin reuptake inhibitor]] (SSRI). By binding to the [[serotonin transporter]] (SERT) it inhibits neuronal [[reuptake]] of [[serotonin]] and potentiates [[Serotonin|serotonergic]] activity in the [[central nervous system]].<ref name="DailyMed" /> Over time, this leads to a downregulation of pre-synaptic [[5-HT1A receptor|5-HT<sub>1A</sub>]] receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of [[brain-derived neurotrophic factor]] (BDNF), which may contribute to a reduction in negative affective biases.<ref>{{cite journal | vauthors = Carhart-Harris RL, Nutt DJ | title = Serotonin and brain function: a tale of two receptors | journal = Journal of Psychopharmacology | volume = 31 | issue = 9 | pages = 1091–1120 | date = September 2017 | pmid = 28858536 | pmc = 5606297 | doi = 10.1177/0269881117725915 }}</ref><ref>{{cite journal | vauthors = Harmer CJ, Duman RS, Cowen PJ | title = How do antidepressants work? New perspectives for refining future treatment approaches | journal = The Lancet. Psychiatry | volume = 4 | issue = 5 | pages = 409–418 | date = May 2017 | pmid = 28153641 | pmc = 5410405 | doi = 10.1016/S2215-0366(17)30015-9 }}</ref> It does not significantly affect [[histamine receptor|histamine]], [[acetylcholine receptor|acetylcholine]], [[GABA receptor|GABA]] or [[benzodiazepine]] receptors.<ref name="DailyMed" />

Sertraline also shows relatively high activity as an inhibitor of the [[dopamine transporter]] (DAT) occupying ~20% of DAT receptors at doses 200mg and above, <ref name="pmid9537821" /><ref name="pmid11357798">{{cite journal | vauthors = Richelson E | title = Pharmacology of antidepressants | journal = Mayo Clinic Proceedings | volume = 76 | issue = 5 | pages = 511–27 | date = May 2001 | pmid = 11357798 | doi = 10.4065/76.5.511 | doi-access = free }}</ref><ref name="HemmingsEgan2012">{{cite book | vauthors = Hemmings HC, Egan TD |title=Pharmacology and Physiology for Anesthesia E-Book: Foundations and Clinical Application|url=https://books.google.com/books?id=am_DS7rgypAC&pg=PA183|date=2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-3793-2|pages=183–}}</ref> and antagonist of the [[sigma receptor|sigma]] [[sigma-1 receptor|σ<sub>1</sub> receptor]] (but not the [[sigma-2 receptor|σ<sub>2</sub> receptor]]).<ref name="AlbayrakHashimoto2017" /><ref name="pmid20373470" /><ref name="pmid20021354">{{cite journal | vauthors = Hashimoto K | title = Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 9 | issue = 3 | pages = 197–204 | date = September 2009 | pmid = 20021354 | doi = 10.2174/1871524910909030197 }}</ref> However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ<sub>1</sub> receptor and DAT.<ref name="PDSP" /><ref name="pmid9537821" /><ref name="pmid20373470" /><ref name="AlbayrakHashimoto2017" /> Although there could be a role for the σ<sub>1</sub> receptor in the [[pharmacology]] of sertraline, the significance of this receptor in its actions is unclear.<ref name="pmid11420570" /> Similarly, the clinical relevance of sertraline's blockade of the dopamine transporter is uncertain.<ref name="pmid9537821" />

===Pharmacokinetics===
[[File:Desmethylsertraline skeletal.svg|class=skin-invert-image|thumb|250px|right|[[Desmethylsertraline]], the major [[metabolite]] of sertaline]]

====Absorption====
Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4&nbsp;hours.<ref name="FDALabel" /> [[Bioavailability]] is likely linear and dose-proportional over a dose range of 150 to 200&nbsp;mg.<ref name="FDALabel" /> Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure.<ref name="FDALabel" /> There is an approximate 2-fold accumulation of sertraline with continuous administration and [[steady state (pharmacokinetics)|steady-state levels]] are reached within one week.<ref name="FDALabel" />

====Distribution====
Sertraline is highly [[plasma protein binding|plasma protein bound]] (98.5%) across a concentration range of 20 to 500&nbsp;ng/mL.<ref name="FDALabel" /> Despite the high plasma protein binding, sertraline and its [[metabolite]] [[desmethylsertraline]] at respective tested concentrations of 300&nbsp;ng/mL and 200&nbsp;ng/mL were found not to interfere with the plasma protein binding of [[warfarin]] and [[propranolol]], two other highly plasma protein-bound drugs.<ref name="FDALabel" />

====Metabolism====
Sertraline is subject to extensive [[first-pass metabolism]], as indicated by a small study of [[radiolabel]]ed sertraline in which less than 5% of plasma [[radioactivity]] was unchanged sertraline in two males.<ref name="FDALabel" /> The principal [[metabolic pathway]] for sertraline is [[demethylation|''N''-demethylation]] into [[desmethylsertraline]] (''N''-desmethylsertraline) mainly by [[CYP2B6]].<ref name="FDALabel" /><ref name="pmid15547048" /> [[Redox|Reduction]], [[hydroxylation]], and [[glucuronidation|glucuronide]] [[conjugation (biochemistry)|conjugation]] of both sertraline and desmethylsertraline also occur.<ref name="FDALabel" /> Desmethylsertraline, while [[pharmacologically active]], is substantially (50-fold) weaker than sertraline as a [[serotonin reuptake inhibitor]] and its influence on the clinical effects of sertraline is thought to be negligible.<ref name="FDALabel" /><ref name="pmid9400006" /><ref name="In Vivo SERT binding">{{cite journal | vauthors = Sprouse J, Clarke T, Reynolds L, Heym J, Rollema H | title = Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo | journal = Neuropsychopharmacology | volume = 14 | issue = 4 | pages = 225–231 | date = April 1996 | pmid = 8924190 | doi = 10.1016/0893-133X(95)00112-Q | ref = 1 | s2cid = 39841365 | doi-access = free }}</ref> Based on ''[[in vitro]]'' studies, sertraline is [[metabolism|metabolized]] by multiple [[cytochrome 450]] [[isoenzyme|isoform]]s;<ref name="pmid15547048" >{{cite journal | vauthors = Obach RS, Cox LM, Tremaine LM | title = Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study | journal = Drug Metabolism and Disposition | volume = 33 | issue = 2 | pages = 262–70 | date = February 2005 | pmid = 15547048 | doi = 10.1124/dmd.104.002428 | s2cid = 7254643 }}</ref><ref name="pmid10383917">{{cite journal | vauthors = Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K | title = Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro | journal = Drug Metabolism and Disposition | volume = 27 | issue = 7 | pages = 763–6 | date = July 1999 | doi = 10.1016/S0090-9556(24)15222-1 | pmid = 10383917 }}</ref> however, it appears that in the human body [[CYP2C19]] plays the most important role, followed by [[CYP2B6]].<ref name="pmid29136336">{{cite journal |vauthors=Saiz-Rodríguez M, Belmonte C, Román M, Ochoa D, Koller D, Talegón M, Ovejero-Benito MC, López-Rodríguez R, Cabaleiro T, Abad-Santos F |title=Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers |journal=Basic & Clinical Pharmacology & Toxicology |volume=122 |issue=5 |pages=501–511 |date=May 2018 |pmid=29136336 |doi=10.1111/bcpt.12938 |doi-access=free |hdl=10261/177557 |hdl-access=free }}</ref> In addition to the cytochrome P450 system, sertraline can be [[oxidation|oxidatively]] [[deamination|deaminated]] ''[[in vitro]]'' by [[monoamine oxidase]]s;<ref name="FDALabel" /> however, this [[metabolic pathway]] has never been studied ''[[in vivo]]''.<ref name="pmid15547048" />

====Elimination====
The [[elimination half-life]] of sertraline is on average 26&nbsp;hours, with a range of 13 to 45&nbsp;hours.<ref name="FDALabel" /><ref name="pmid12452737">{{cite journal |vauthors=DeVane CL, Liston HL, Markowitz JS |title=Clinical pharmacokinetics of sertraline |journal=Clin Pharmacokinet |volume=41 |issue=15 |pages=1247–66 |date=2002 |pmid=12452737 |doi=10.2165/00003088-200241150-00002 |s2cid=28720641 }}</ref> The elimination half-life of desmethylsertraline is 62 to 104&nbsp;hours.<ref name="FDALabel" />

In a small study of two males, sertraline was [[excretion|excreted]] to similar degrees in [[urine]] and [[feces]] (40 to 45% each within 9&nbsp;days).<ref name="FDALabel" /> Unchanged sertraline was not detectable in urine, whereas 12 to 14% of unchanged sertraline was present in feces.<ref name="FDALabel" />

===Pharmacogenomics===
[[CYP2C19]] and [[CYP2B6]] are thought to be the key [[cytochrome P450]] [[enzyme]]s involved in the [[metabolism]] of sertraline.<ref name="pmid29136336" /> Relative to CYP2C19 [[extensive metabolizer|normal (extensive) metabolizer]]s, [[poor metabolizer]]s have 2.7-fold higher levels of sertraline<ref name="pmid31649299">{{cite journal |vauthors=Bråten LS, Haslemo T, Jukic MM, Ingelman-Sundberg M, Molden E, Kringen MK |title=Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients |journal=Neuropsychopharmacology |volume=45 |issue=3 |pages=570–576 |date=February 2020 |pmid=31649299 |doi=10.1038/s41386-019-0554-x |pmc=6969041 }}</ref> and [[intermediate metabolizer]]s have 1.4-fold higher levels.<ref name="pmid33237321">{{cite journal |vauthors=Milosavljevic F, Bukvic N, Pavlovic Z, Miljevic C, Pešic V, Molden E, Ingelman-Sundberg M, Leucht S, Jukic MM |title=Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis |journal=JAMA Psychiatry |date=November 2020 |volume=78 |issue=3 |pages=270–280 |pmid=33237321 |doi=10.1001/jamapsychiatry.2020.3643 |pmc=7702196 }}</ref> In contrast, CYP2B6 poor metabolizers have 1.6-fold higher levels of sertraline and intermediate metabolizers have 1.2-fold higher levels.<ref name="pmid29136336" />