Editing Tetrahydrocannabinol (section)

===Pharmacokinetics===
====Absorption====
With oral administration of a single dose, THC is almost completely [[absorption (pharmacokinetics)|absorbed]] by the [[gastrointestinal tract]].<ref name="MarinolLabel2023">{{Cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/018651s033lbl.pdf | title=Highlights of prescribing information | website=www.accessdata.fda.gov}}</ref> However, due to [[first-pass metabolism]] in the [[liver]] and the high [[lipid solubility]] of THC, only about 5 to 20% reaches circulation.<ref name="pmid12648025" /><ref name="MarinolLabel2023" /> Following oral administration, concentrations of THC and its major [[active metabolite]] [[11-hydroxy-THC]] (11-OH-THC) [[Tmax (pharmacology)|peak]] after 0.5 to 4{{nbsp}}hours, with median time to peak of 1.0 to 2.5{{nbsp}}hours at different doses.<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> In some cases, peak levels may not occur for as long as 6{{nbsp}}hours.<ref name="pmid12648025" /> Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration.<ref name="MarinolLabel2023" /> There is a slight increase in [[dose proportionality]] in terms of [[Cmax (pharmacology)|peak]] and [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] levels of THC with increasing oral doses over a range of 2.5 to 10{{nbsp}}mg.<ref name="MarinolLabel2023" /> A high-fat meal delays time to peak concentrations of oral THC by 4{{nbsp}}hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.<ref name="MarinolLabel2023" /> A high-fat meal additionally increases absorption of THC via the [[lymphatic system]] and allows it to bypass first-pass metabolism.<ref name="pmid35523678">{{cite journal | vauthors = Tagen M, Klumpers LE | title = Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC | journal = Br J Pharmacol | volume = 179 | issue = 15 | pages = 3915–3933 | date = August 2022 | pmid = 35523678 | doi = 10.1111/bph.15865 | url = | doi-access = free }}</ref> Consequently, a high-fat meal increases levels of 11-hydroxy-THC by only 25% and most of the increase in [[bioavailability]] is due to increased levels of THC.<ref name="pmid35523678" />

The bioavailability of THC when [[smoking]] or [[inhalational administration|inhaling]] is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%).<ref name="pmid30001569">{{cite journal | vauthors = Lucas CJ, Galettis P, Schneider J | title = The pharmacokinetics and the pharmacodynamics of cannabinoids | journal = Br J Clin Pharmacol | volume = 84 | issue = 11 | pages = 2477–2482 | date = November 2018 | pmid = 30001569 | pmc = 6177698 | doi = 10.1111/bcp.13710 | url = }}</ref><ref name="pmid31152723">{{cite journal | vauthors = Foster BC, Abramovici H, Harris CS | title = Cannabis and Cannabinoids: Kinetics and Interactions | journal = Am J Med | volume = 132 | issue = 11 | pages = 1266–1270 | date = November 2019 | pmid = 31152723 | doi = 10.1016/j.amjmed.2019.05.017 | s2cid = 173188471 | url = }}</ref><ref name="pmid12648025" /> The large range and marked [[interindividual variability|variability between individuals]] is due to variation in factors including product matrix, ignition temperature, and inhalational dynamics (e.g., number, duration, and intervals of inhalations, breath hold time, depth and volume of inhalations, size of inhaled particles, deposition site in the lungs).<ref name="pmid30001569" /><ref name="pmid31152723" /> THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10{{nbsp}}minutes.<ref name="pmid12648025" /><ref name="pmid31152723" /> Smoking or inhaling THC results in greater blood levels of THC and its metabolites and a much faster [[onset of action]] than oral administration of THC.<ref name="pmid30001569" /><ref name="pmid31152723" /> Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" /> The bioavailability of THC with inhalation is increased in heavy users.<ref name="pmid12648025" />

[[Transdermal administration]] of THC is limited by its extreme [[hydrophobicity|water insolubility]].<ref name="pmid30001569" /> Efficient skin transport can only be obtained with permeation enhancement.<ref name="pmid30001569" /> Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" />

====Distribution====
The [[volume of distribution]] of THC is large and is approximately 10{{nbsp}}L/kg (range 4–14{{nbsp}}L/kg), which is due to its high lipid solubility.<ref name="MarinolLabel2023" /><ref name="pmid30001569" /><ref name="pmid31152723" /> The [[plasma protein binding]] of THC and its [[metabolite]]s is approximately 95 to 99%, with THC bound mainly to [[lipoprotein]]s and to a lesser extent [[human serum albumin|albumin]].<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> THC is rapidly distributed into well-vascularized organs such as [[lung]], [[heart]], [[brain]], and [[liver]], and is subsequently equilibrated into less vascularized tissue.<ref name="pmid30001569" /><ref name="pmid31152723" /> It is extensively distributed into and sequestered by [[adipose tissue|fat tissue]] due to its high lipid solubility, from which it is slowly released.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="pmid31152723" /> THC is able to cross the [[placenta]] and is excreted in human [[breast milk]].<ref name="pmid30001569" /><ref name="pmid12648025" />

====Metabolism====
The [[metabolism]] of THC occurs mainly in the [[liver]] by [[cytochrome P450]] [[enzyme]]s [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]].<ref>{{cite journal | vauthors = Qian Y, Gurley BJ, Markowitz JS | title = The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications | journal = Journal of Clinical Psychopharmacology | volume = 39 | issue = 5 | pages = 462–71 | year = 2019 | pmid = 31433338 | doi = 10.1097/JCP.0000000000001089 | s2cid = 201118659 }}</ref><ref>{{cite journal | vauthors = Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I | title = Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes | journal = Life Sciences | volume = 80 | issue = 15 | pages = 1415–19 | date = March 2007 | pmid = 17303175 | doi = 10.1016/j.lfs.2006.12.032 }}</ref> CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC.<ref name="MarinolLabel2023" /> [[Pharmacogenomic]] research has found that oral THC exposure is 2- to 3-fold greater in people with [[Gene polymorphism|genetic variant]]s associated with reduced CYP2C9 function.<ref name="MarinolLabel2023" /> When taken orally, THC undergoes extensive [[first-pass metabolism]] in the liver, primarily via [[hydroxylation]].<ref name="MarinolLabel2023" /> The principal active metabolite of THC is [[11-hydroxy-THC]] (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="MarinolLabel2023" /> This metabolite is further [[oxidation|oxidized]] to [[11-nor-9-carboxy-THC]] (THC-COOH). In animals, more than 100 metabolites of THC could be identified, but 11-OH-THC and THC-COOH are the predominant metabolites.<ref name="pmid35523678" /><ref name="pmid27341312">{{cite journal | vauthors = Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A | title = Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis | journal = Drug Testing and Analysis | volume = 9 | issue = 4 | pages = 626–33 | date = April 2017 | pmid = 27341312 | doi = 10.1002/dta.1998 | s2cid = 27488987 | url = https://figshare.com/articles/journal_contribution/5028359 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025824/https://figshare.com/articles/journal_contribution/Simultaneous_quantification_of_major_cannabinoids_and_metabolites_in_human_urine_and_plasma_by_HPLC-MS_MS_and_enzymealkaline_hydrolysis/5028359 | url-status = live }}</ref>

====Elimination====
More than 55% of THC is [[excretion|excreted]] in the [[feces]] and approximately 20% in the [[urine]]. The main metabolite in urine is the ester of [[glucuronic acid]] and 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.<ref name="pmid16596792">{{cite journal | vauthors = Huestis MA | title = Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ<sup>9</sup>-Tetrahydrocannabinol, Cannabidiol and Cannabinol | journal = Handbook of Experimental Pharmacology | volume = 168 | issue = 168 | pages = 657–90 | year = 2005 | pmid = 16596792 | doi = 10.1007/3-540-26573-2_23 | isbn = 978-3-540-22565-2}}</ref>

Estimates of the [[elimination half-life]] of THC are variable.<ref name="pmid30001569" /> THC was reported to have a fast initial half-life of 6{{nbsp}}minutes and a long [[terminal half-life]] of 22{{nbsp}}hours in a [[Pharmacokinetics#Population pharmacokinetics|population pharmacokinetic]] study.<ref name="pmid30001569" /><ref name="pmid31152723" /> Conversely, the [[Food and Drug Administration]] label for dronabinol reports an initial half-life of 4{{nbsp}}hours and a terminal half-life of 25 to 36{{nbsp}}hours.<ref name="MarinolLabel2023" /> Many studies report an elimination half-life of THC in the range of 20 to 30{{nbsp}}hours.<ref name="pmid12648025" /> 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36{{nbsp}}hours relative to 25 to 36{{nbsp}}hours in one study.<ref name="pmid12648025" /> The elimination half-life of THC is longer in heavy users.<ref name="pmid30001569" /> This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.<ref name="pmid30001569" />