Editing Modafinil (section)

==Pharmacology==
===Pharmacodynamics===
{| class="wikitable floatright"
|+ Modafinil activity profile
|-
! Site !! Potency !! Type !! Species !! Refs
|-
| {{Abbrlink|DAT|Dopamine transporter}} || {{Val|1.8|-|2.6|u=μM}}<br />{{Val|4.8|u=μM}}<br />{{Val|6.4|u=μM}}<br />{{Val|4.0|u=μM}}|| K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub><sup>a</sup><br />IC<sub>50</sub><sup>a</sup> || Human<br />Rat<br />Human<br />Rat || <ref name="pmid19197004">{{cite journal | vauthors = Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH | title = Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 329 | issue = 2 | pages = 738–746 | date = May 2009 | pmid = 19197004 | pmc = 2672878 | doi = 10.1124/jpet.108.146142 | author5-link = Bryan Roth }}</ref><ref name="pmid34423920">{{cite journal | vauthors = Krief S, Berrebi-Bertrand I, Nagmar I, Giret M, Belliard S, Perrin D, Uguen M, Robert P, Lecomte JM, Schwartz JC, Finance O, Ligneau X | title = Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol | journal = Pharmacology Research & Perspectives | volume = 9 | issue = 5 | pages = e00855 | date = October 2021 | pmid = 34423920 | pmc = 8381683 | doi = 10.1002/prp2.855 }}</ref><br /><ref name="pmid19197004" /><br /><ref name="pmid29115823">{{cite journal | vauthors = Murillo-Rodríguez E, Barciela Veras A, Barbosa Rocha N, Budde H, Machado S | title = An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil | journal = ACS Chemical Neuroscience | volume = 9 | issue = 2 | pages = 151–158 | date = February 2018 | pmid = 29115823 | doi = 10.1021/acschemneuro.7b00374 }}</ref><ref name="pmid22537794">{{cite journal | vauthors = Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, Kopajtic T, Shi L, Katz JL, Tanda G, Newman AH | title = R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse | journal = Biological Psychiatry | volume = 72 | issue = 5 | pages = 405–413 | date = September 2012 | pmid = 22537794 | pmc = 3413742 | doi = 10.1016/j.biopsych.2012.03.022 }}</ref><br /><ref name="pmid19197004" />
|-
| {{Abbrlink|NET|Norepinephrine transporter}} || &gt;{{Val|10|u=μM}}<br />&gt;{{Val|92|u=μM}}<br />{{Val|35.6|u=μM}}<br />{{Val|136|u=μM}} || K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub><sup>a</sup><br />IC<sub>50</sub><sup>a</sup> || Human<br />Rat<br />Human<br />Rat || <ref name="pmid19197004" /><ref name="pmid34423920" /><br /><ref name="pmid19197004" /><br /><ref name="pmid29115823" /><ref name="pmid22537794" /><br /><ref name="pmid19197004" />
|-
| {{Abbrlink|SERT|Serotonin transporter}} || >{{Val|10|u=μM}}<br />{{Val|46.6|u=μM}}<br />&gt;{{Val|500|u=μM}}<br />&gt;{{Val|50|u=μM}} || K<sub>i</sub><br />K<sub>i</sub><br />IC<sub>50</sub><sup>a</sup><br />IC<sub>50</sub><sup>a</sup> || Human<br />Rat<br />Human<br />Rat || <ref name="pmid19197004" /><ref name="pmid34423920" /><br /><ref name="pmid19197004" /><br /><ref name="pmid29115823" /><ref name="pmid22537794" /><br /><ref name="pmid19197004" />
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || >{{Val|10|u=μM}}<br />{{Val|16|u=μM}}<sup>b</sup><br />{{Val|120|u=μM}}<sup>b</sup> || K<sub>i</sub><br />K<sub>i</sub><br />EC<sub>50</sub><sup>a</sup> || Human<br />Rat<br />Rat|| <ref name="pmid19197004" /><br /><ref name="pmid19391150">{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }}</ref><br /><ref name="pmid19391150" />
|- class="sortbottom"
| colspan="5" style="width:1px; background:#eaecf0; text-align:center;"| '''Footnotes:''' <sup>a</sup> = Functional activity, not binding inhibition. <sup>b</sup> = [[Armodafinil]] at D<sub>2</sub><sup>High</sup>. '''Notes:''' No activity at a variety of other assessed targets.<ref name="pmid19197004" />
|}

The precise [[mechanism of action]] of modafinil for narcolepsy and other sleep disorders remains unclear.<ref name="Drugs.com-Monograph-2023"/><ref name="pmid32032921">{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | s2cid = 203405397 }}</ref><ref name="Stahl-2017">{{cite book | vauthors=Stahl SM | title=Prescriber's Guide: Stahl's Essential Psychopharmacology | date=March 2017 | publisher=Cambridge University Press | location=Cambridge, United Kingdom | isbn=978-1-108-22874-9 | pages=491–495 | edition=6th | chapter=Modafinil }}</ref><ref name="pmid19300566">{{cite journal | vauthors = Gerrard P, Malcolm R | title = Mechanisms of modafinil: A review of current research | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 3 | pages = 349–364 | date = June 2007 | pmid = 19300566 | pmc = 2654794 }}</ref> Although modafinil may have interactions with neurotransmitter systems, its exact mode of action is not fully understood.<ref name="pmid32032921"/><ref name="pmid28646346">{{cite book | vauthors = Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB | chapter = Adenosine and Sleep | title = Handbook of Experimental Pharmacology | volume = 253 | pages = 359–381 | date = 2019 | pmid = 28646346 | doi = 10.1007/164_2017_36 | isbn = 978-3-030-11270-7 }}</ref>

From laboratory research, modafinil has little to no affinity for [[Serotonin transporter|serotonin]] or [[norepinephrine transporter]]s and does not directly interact with these systems.<ref name="pmid30285371"/><ref name="pmid19300566"/> However, studies have shown that elevated concentrations of norepinephrine and serotonin can occur as an indirect effect following modafinil administration due to increased extracellular dopamine activity.<ref name="pmid19300566"/><ref name="pmid30285371"/> Unlike traditional psychostimulant drugs,<ref name="pmid38725665"/> such as [[cocaine]] or [[amphetamine]], modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level.<ref name="pmid32032921"/><ref name="pmid19300566"/><ref name="pmid28646346"/>

In addition to its influence on [[dopaminergic pathways]], modafinil may impact other neurotransmitter systems, such as [[orexin]] ([[hypocretin]]).<ref name="pmid19300566"/> Orexin neurons are involved in promoting wakefulness and regulating arousal states. Modafinil may increase signaling within hypothalamic orexin pathways, potentially contributing to its wake-promoting effects.<ref name="pmid30285371"/><ref name="pmid19300566"/>

===Pharmacokinetics===
C<sub>max</sub> (peak levels) occurs approximately 2&nbsp;to&nbsp;3&nbsp;hours after modafinil administration.<ref name="pmid12537513"/> Food slows the absorption of modafinil but does not affect the total [[Area under the curve (pharmacokinetics)|area under the curve]] (AUC). ''In vitro'' measurements indicate that 60% of modafinil is bound to [[plasma protein]]s at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.<ref name="Hardman2001">{{cite book |vauthors=Gilman A, Goodman LS, Hardman JG, Limbird LE |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2001 |page=1984 |isbn=978-0-07-135469-1 }}</ref>

Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, the only approved route of administration, less than 10% of the drug is eliminated from the body through the urine without being metabolized by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.<ref name="pmid12537513"/>

The two major circulating [[metabolite]]s of modafinil are [[modafinil acid]] (CRL-40467) and [[modafinil sulfone]] (CRL-41056). Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil.<ref name="pmid31951804"/><ref name="pmid26908128">{{cite journal | vauthors = Ramachandra B | title = A Critical Review of Properties of Modafinil and Analytical, Bioanalytical Methods for its Determination | journal = Critical Reviews in Analytical Chemistry | volume = 46 | issue = 6 | pages = 482–489 | date = November 2016 | pmid = 26908128 | doi = 10.1080/10408347.2016.1153948 | s2cid = 34069997 }}</ref> However, modafinil sulfone does appear to possess [[anticonvulsant]] effects, a property that it shares with modafinil.<ref name="pmid31951804"/><ref name="pmid15260124">{{cite journal | vauthors = Chatterjie N, Stables JP, Wang H, Alexander GJ | title = Anti-narcoleptic agent modafinil and its sulfone: a novel facile synthesis and potential anti-epileptic activity | journal = Neurochemical Research | volume = 29 | issue = 8 | pages = 1481–1486 | date = August 2004 | pmid = 15260124 | doi = 10.1023/b:nere.0000029559.20581.1a | s2cid = 956077 }}</ref>

[[Elimination half-life]] is in the range of 10 to 12 hours,<ref name="pmid12537513"/><ref name="Hardman2001"/> subject to differences in sex,<ref name="sleep-women-2016"/> in cytochrome P450 [[genotype]]s, liver function and renal function. Modafinil is metabolized mainly in the liver,<ref name="pmid12537513"/> and its inactive metabolites are excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10% but can range from 0% to as high as 18.7%, depending on the factors mentioned.<ref name="Hardman2001"/>

Modafinil exhibits sex-specific pharmacokinetic differences.<ref name="sleep-women-2016" /> It demonstrates higher [[bioavailability]] in women compared to men. The mean C<sub>max</sub> is higher in women than in men, {{Val|5.2|u=mg/L}} vs. {{Val|4.2|u=mg/L}} (p < 0.05), following a single {{Val|200|u=mg}} oral dose of modafinil.<ref name="sleep-women-2016" /> This difference persists even after adjusting for body weight ({{Val|0.88|u=ml/min/kg}} vs. {{Val|0.72|u=ml/min/kg}}).<ref name="sleep-women-2016" /> The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men. These sex-specific pharmacokinetic differences may have implications for the efficacy and safety of modafinil.<ref name="sleep-women-2016" />