Editing Oxycodone (section)

====Metabolism====
The [[metabolism]] of oxycodone in humans occurs in the [[liver]] mainly via the [[cytochrome P450]] system and is extensive (about 95%) and complex, with many minor [[metabolic pathway|pathway]]s and resulting [[metabolite]]s.<ref name="SmithPassik2008" /><ref name="pmid14516487">{{cite journal | vauthors = Moore KA, Ramcharitar V, Levine B, Fowler D | title = Tentative identification of novel oxycodone metabolites in human urine | journal = Journal of Analytical Toxicology | volume = 27 | issue = 6 | pages = 346–352 | date = September 2003 | pmid = 14516487 | doi = 10.1093/jat/27.6.346 | doi-access = free }}</ref> Around 10% (range 8–14%) of a dose of oxycodone is excreted essentially unchanged (unconjugated or [[conjugation (biochemistry)|conjugated]]) in the [[urine]].<ref name="SmithPassik2008"/> The major metabolites of oxycodone are [[noroxycodone]] (70%), [[noroxymorphone]] ("relatively high concentrations"),<ref name="FitzgibbonLoeser2012">{{cite book| vauthors = Fitzgibbon DR, Loeser JD |title=Cancer Pain|url=https://books.google.com/books?id=17vaJQVtDN0C&pg=PA198|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5279-1|pages=198–}}</ref> and [[oxymorphone]] (5%).<ref name="LalovicKharasch2006" /><ref name="Preedy2016">{{cite book| vauthors = Preedy VR |title=Neuropathology of Drug Addictions and Substance Misuse Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions|url=https://books.google.com/books?id=Yu9eBwAAQBAJ&pg=PA462|date=25 April 2016|publisher=Elsevier Science|isbn=978-0-12-800677-1|pages=462–464}}</ref> The immediate metabolism of oxycodone in humans is as follows:<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" >{{cite book | vauthors = McPherson RA, Pincus MR |title=Henry's Clinical Diagnosis and Management by Laboratory Methods |url=https://books.google.com/books?id=xAzhCwAAQBAJ&pg=PA336 |date=31 March 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-41315-2 |pages=336–}}</ref><ref name="AnzenbacherZanger2012">{{cite book|vauthors=Anzenbacher P, Zanger UM|title=Metabolism of Drugs and Other Xenobiotics|url=https://books.google.com/books?id=ulcB7zYIresC&pg=PA420|date=29 May 2012|publisher=John Wiley & Sons|isbn=978-3-527-32903-8|pages=420–|access-date=5 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007000913/https://books.google.com/books?id=ulcB7zYIresC&pg=PA420|url-status=live}}</ref>

* N-[[Demethylation]] to [[noroxycodone]] predominantly via [[CYP3A4]]
* O-Demethylation to [[oxymorphone]] predominantly via [[CYP2D6]]
* 6-[[wikt:ketoreduction|Ketoreduction]] to [[6α-oxycodol|6α-]] and [[6β-oxycodol]]
* N-[[Oxidation]] to [[oxycodone-N-oxide]]

In humans, N-demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of oxycodone, while O-demethylation of oxycodone into oxymorphone by CYP2D6 and 6-ketoreduction of oxycodone into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of oxycodone, respectively.<ref name="SmithPassik2008"/><ref name="Davis2009" />

Several of the immediate metabolites of oxycodone are subsequently conjugated with [[glucuronic acid]] and excreted in the [[urine]].<ref name="SmithPassik2008"/> 6α-Oxycodol and 6β-oxycodol are further metabolized by N-demethylation to [[nor-6α-oxycodol]] and [[nor-6β-oxycodol]], respectively, and by N-oxidation to [[6α-oxycodol-N-oxide]] and [[6β-oxycodol-N-oxide]] (which can subsequently be [[glucuronidation|glucuronidated]] as well).<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" /> Oxymorphone is also further metabolized, as follows:<ref name="SmithPassik2008"/><ref name="McPhersonPincus2016" /><ref name="AnzenbacherZanger2012" />

* 3-Glucuronidation to [[oxymorphone-3-glucuronide]] predominantly via [[UGT2B7]]
* 6-Ketoreduction to [[oxymorphol|6α-oxymorphol]] and [[oxymorphol|6β-oxymorphol]]
* N-Demethylation to [[noroxymorphone]]

The first pathway of the above three accounts for 40% of the metabolism of oxymorphone, making oxymorphone-3-glucuronide the main metabolite of oxymorphone, while the latter two pathways account for less than 10% of the metabolism of oxymorphone.<ref name="AnzenbacherZanger2012" /> After N-demethylation of oxymorphone, [[noroxymorphone]] is further glucuronidated to [[noroxymorphone-3-glucuronide]].<ref name="AnzenbacherZanger2012" />

Because oxycodone is metabolized by the cytochrome P450 system in the liver, its pharmacokinetics can be influenced by [[genetic polymorphism]]s and [[drug interaction]]s concerning this system, as well as by [[liver function]].<ref name="OxyContinInsertUS" /> Some people are [[fast metabolizer]]s of oxycodone, while others are [[slow metabolizer]]s, resulting in polymorphism-dependent alterations in relative analgesia and toxicity.<ref name="pmid15625333">{{cite journal | vauthors = Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J | title = Codeine intoxication associated with ultrarapid CYP2D6 metabolism | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2827–2831 | date = December 2004 | pmid = 15625333 | doi = 10.1056/NEJMoa041888 | doi-access = free }}</ref><ref name="pmid8477556">{{cite journal | vauthors = Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM | title = Inhibition by fluoxetine of cytochrome P450 2D6 activity | journal = Clinical Pharmacology and Therapeutics | volume = 53 | issue = 4 | pages = 401–409 | date = April 1993 | pmid = 8477556 | doi = 10.1038/clpt.1993.43 | s2cid = 39724277 }}</ref> While higher CYP2D6 activity increases the effects of oxycodone (owing to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect and decreases the effects of oxycodone (owing to increased metabolism into noroxycodone and noroxymorphone).<ref name="SamerDaali2010">{{cite journal | vauthors = Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier MF, Hochstrasser D, Dayer P, Desmeules JA | title = Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety | journal = British Journal of Pharmacology | volume = 160 | issue = 4 | pages = 919–930 | date = June 2010 | pmid = 20590588 | pmc = 2935998 | doi = 10.1111/j.1476-5381.2010.00709.x }}</ref> The dose of oxycodone must be reduced in patients with [[hepatic impairment|reduced liver function]].<ref name=AHFS>{{cite web |title=Oxycodone |url=https://www.drugs.com/monograph/oxycodone.html |work=The American Society of Health-System Pharmacists |access-date=3 April 2011 |archive-date=28 December 2018 |archive-url=https://web.archive.org/web/20181228174726/https://www.drugs.com/monograph/oxycodone.html |url-status=live }}</ref>