Editing Oxycodone (section)

===Pharmacokinetics===

====Instant-release absorption profiles and Tmax====
Oxycodone can be administered orally, intravenously, via [[intravenous]], [[intramuscular]], or [[subcutaneous injection]]. Along with [[suppository|rectal]], [[sublingual]], [[Buccal administration|buccal]] or [[intranasal drug delivery]]. The [[bioavailability]] of [[oral administration]] of oxycodone averages within a range of 60 to 87%, with rectal administration yielding the same results; [[Intranasal]] administration of oxycodone has a bioavailability of ~77%, the same [[half life]] as oral oxycodone, along with faster [[Tmax (pharmacology)|Tmax]]<ref>{{cite journal | vauthors = Lofwall MR, Moody DE, Fang WB, Nuzzo PA, Walsh SL | title = Pharmacokinetics of intranasal crushed OxyContin and intravenous oxycodone in nondependent prescription opioid abusers | journal = Journal of Clinical Pharmacology | volume = 52 | issue = 4 | pages = 600–606 | date = April 2012 | pmid = 21610203 | pmc = 4006196 | doi = 10.1177/0091270011401620 }}</ref> previously reported as 47% for nasal spray administration due to the solution in the study exceeding the 0.3- to 0.4-mL nasal mucosa limit.<ref>Analgesic Expert Group. Therapeutic Guidelines: Analgesic. Version 4. Melbourne: Therapeutic Guidelines Ltd, 2007.</ref> Buccal bioavailability ~55%, [[Tmax (pharmacology)|Tmax]] ~60 min.<ref>{{cite journal | vauthors = Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M | title = Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone | journal = Clinical Pharmacokinetics | volume = 58 | issue = 6 | pages = 705–725 | date = June 2019 | pmid = 30652261 | doi = 10.1007/s40262-018-00731-3 | quote = Data indicate that after buccal and sublingual administration of oxycodone 0.1 mg/kg, the rate and extent of absorption is appropriate for clinical use. After transmucosal administration, C<sub>max</sub> was between 16 and 22 ng/mL, T<sub>max</sub> was 60 min, and bioavailability was 55% | doi-access = free }}</ref> Sublingual bioavailability 20% (non alkalized) ~55% (alkalized) [[Tmax (pharmacology)|Tmax]] ~60 minutes.<ref>{{cite journal | vauthors = Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M | title = Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone | journal = Clinical Pharmacokinetics | volume = 58 | issue = 6 | pages = 705–725 | date = June 2019 | pmid = 30652261 | doi = 10.1007/s40262-018-00731-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li Y, Sun D, Palmisano M, Zhou S | title = Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations | journal = Pharmacology Research & Perspectives | volume = 4 | issue = 1 | pages = e00210 | date = February 2016 | pmid = 26977300 | pmc = 4777261 | doi = 10.1002/prp2.210 }}</ref>

After a dose of conventional (immediate-release) oral oxycodone, the [[onset of action]] is 10 to 30 minutes,<ref name="SmithPassik2008"/><ref name="ElliottSmith2016" /> and peak plasma levels of the drug are attained within roughly 30 to 60 minutes;<ref name="SmithPassik2008"/><ref name="ElliottSmith2016" /><ref name="LalovicKharasch2006" /> in contrast, after a dose of OxyContin (an oral controlled-release formulation), [[peak plasma levels]] of oxycodone occur in about three hours.<ref name="OxyContinInsertUS">{{cite book|title=1. Package insert Oxycontin|publisher=Purdue Pharma L.P|date=5 November 2007|location=Stamfbord, CT|url=http://www.purduepharma.com/PI/Prescription/Oxycontin.pdf|access-date=23 March 2009|url-status=dead|archive-url=https://web.archive.org/web/20090326125214/http://www.purduepharma.com/PI/Prescription/Oxycontin.pdf|archive-date=26 March 2009}}</ref> The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.<ref name="SmithPassik2008"/>

====Distribution====
Oxycodone has a [[volume of distribution]] of 2.6L/kg,<ref name="Drugbank">{{cite web |title=Oxycodone |url=https://www.drugbank.ca/drugs/DB00497 |website=www.drugbank.ca |access-date=24 January 2019 |archive-date=25 January 2019 |archive-url=https://web.archive.org/web/20190125074846/https://www.drugbank.ca/drugs/DB00497 |url-status=live }}</ref> in the blood it is distributed to [[skeletal muscle]], liver, intestinal tract, lungs, [[spleen]], and brain.<ref name="OxyContinInsertUS" /> At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood.<ref>{{cite journal | vauthors = Boström E, Simonsson US, Hammarlund-Udenaes M | title = In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics | journal = Drug Metabolism and Disposition | volume = 34 | issue = 9 | pages = 1624–1631 | date = September 2006 | pmid = 16763013 | doi = 10.1124/dmd.106.009746 | s2cid = 772550 }}</ref> Conventional oral preparations start to reduce pain within 10 to 15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour.<ref name=AHFS2018/>

====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>

====Elimination====
The clearance of oxycodone is 0.8&nbsp;L/min.<ref name="Drugbank"/> Oxycodone and its metabolites are mainly [[excretion|excreted]] in urine.<ref name="DavisCladis2016">{{cite book| vauthors = Davis PJ, Cladis FP |title=Smith's Anesthesia for Infants and Children E-Book |url=https://books.google.com/books?id=SGljDQAAQBAJ&pg=PA234 |date=15 October 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-38869-6 |pages=234–}}</ref> Therefore, oxycodone accumulates in patients with [[renal|kidney]] impairment.<ref name="AHFS" /> Oxycodone is [[elimination (pharmacology)|eliminated]] in the urine 10% as unchanged oxycodone, 45% ± 21% as ''N''-demethylated metabolites (noroxycodone, noroxymorphone, noroxycodols), 11 ± 6% as ''O''-demethylated metabolites (oxymorphone, oxymorphols), and 8% ± 6% as 6-keto-reduced metabolites (oxycodols).<ref name="DavisCladis2016" /><ref name="LalovicKharasch2006"/>

====Duration of action====
Oral oxycodone has a half-life of 4.5 hours.<ref name="Drugbank"/> It is available as a [[generic medication]].<ref name="AHFS2018" /> The manufacturer of OxyContin, a controlled-release preparation of oxycodone, [[Purdue Pharma]], claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in "90% of patients". It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release oxycodone "provides pain relief in said patient for at least 12 hours after administration".<ref name="latimes2016">{{cite news |vauthors=Ryan H, Girion L, Glover S |title=You want a description of hell?' OxyContin's 12-hour problem |url=https://www.latimes.com/projects/oxycontin-part1/ |access-date=8 July 2018 |work=Los Angeles Times |date=7 July 2016 |archive-date=1 July 2018 |archive-url=https://web.archive.org/web/20180701135355/http://www.latimes.com/projects/oxycontin-part1/ |url-status=live }}</ref> However, in 2016 an investigation by the ''[[Los Angeles Times]]'' found that "the drug wears off hours early in many people", inducing symptoms of [[opiate withdrawal]] and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they complained that the duration of action for OxyContin was too short to be taken only twice a day.<ref name="latimes2016"/><ref name="oxycontinfiles">{{cite news |title='Q12' Workshops, 2001 |url=http://documents.latimes.com/q12-workshops-2001/ |newspaper=Los Angeles Times |access-date=8 July 2018 |archive-date=21 April 2018 |archive-url=https://web.archive.org/web/20180421121121/http://documents.latimes.com/q12-workshops-2001/ |url-status=live }}</ref> Mean serum concentration of controlled-release oxycodone peaks at 78 ng/ml at 1 hour and drops to 20 ng/ml at 8 hours and under 10 ng/ml at 12 hours.<ref name="DDD13.8" />

Purdue strongly discouraged the practice: Purdue's medical director Robert Reder wrote to one doctor in 1995 that " OxyContin has been developed for [12-hour] dosing...I request that you not use a [8-hourly] dosing regimen." Purdue repeatedly released memos to its sales representatives ordering them to remind doctors not to deviate from a 12-hour dosing schedule. One such memo read, "There is no Q8 dosing with OxyContin... [8-hour dosing] needs to be nipped in the bud. NOW!!"<ref name="latimes2016"/> The journalists who covered the investigation argued that Purdue Pharma has insisted on a 12-hour duration of action for nearly all patients, despite evidence to the contrary, to protect the reputation of OxyContin as a 12-hour drug and the willingness of [[health insurance]] and [[managed care]] companies to cover OxyContin despite its high cost relative to generic opiates such as morphine.<ref name="latimes2016"/>

Purdue sales representatives were instructed to encourage doctors to write prescriptions for larger 12-hour doses instead of more frequent dosing. An August 1996 memo to Purdue sales representatives in Tennessee entitled "$$$$$$$$$$$$$ It's Bonus Time in the Neighborhood!" reminded the representatives that their commissions would dramatically increase if they were successful in convincing doctors to prescribe larger doses. ''Los Angeles Times'' journalists argue using interviews from opioid addiction experts that such high doses of OxyContin spaced 12 hours apart create a combination of agony during opiate withdrawal (lower lows) and a [[schedule of reinforcement]] that relieves this agony fostering addiction.<ref name="latimes2016"/>

As of 2024, the [[Medication package insert|prescribing information]] for OxyContin still specifies a controversial 12-hour dosing schedule - which experts say promotes addiction - as the only option;<ref name="Oxycontin FDA label" /><ref>{{Cite web |title=OxyContin Investigation |url=https://www.latimes.com/projects/la-me-oxycontin-full-coverage/ |access-date=2025-03-08 |website=www.latimes.com |language=en}}</ref> it also still states, "there are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours."<ref name="Oxycontin FDA label" />