Editing Hydrocodone (section)

===Pharmacokinetics===

====Absorption====
Hydrocodone is only pharmaceutically available as an [[oral administration|oral]] medication.<ref name="ElliottSmith2016" /> It is well-[[absorption (pharmacokinetics)|absorbed]], but the oral [[bioavailability]] of hydrocodone is only approximately 25%.<ref name="FiresteinBudd2016" /><ref name="ChabnerLongo2010" /> The [[onset of action]] of hydrocodone via this route is 10 to 20&nbsp;minutes, with a peak effect ([[Tmax (pharmacology)|T<sub>max</sub>]]) occurring at 30 to 60&nbsp;minutes,<ref name="King2010" /> and it has a duration of 4 to 8 hours.<ref name="ElliottSmith2016" /> The FDA label for immediate-release hydrocodone with acetaminophen does not include any information on the influence of food on its absorption or other pharmacokinetics.<ref name="Norco-FDA-Label-2019">[https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/040099s023lbl.pdf Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg CII] {{Webarchive|url=https://web.archive.org/web/20240222220916/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/040099s023lbl.pdf |date=22 February 2024 }} fda.gov</ref> Conversely, coadministration with a high-fat meal increases peak concentrations of different formulations of extended-release hydrocodone by 14 to 54%, whereas [[area-under-the-curve levels]] are not notably affected.<ref name="pmid28635354">{{cite journal | vauthors = Raffa RB, Colucci R, Pergolizzi JV | title = The effects of food on opioid-induced nausea and vomiting and pharmacological parameters: a systematic review | journal = Postgraduate Medicine | volume = 129 | issue = 7 | pages = 698–708 | date = September 2017 | pmid = 28635354 | doi = 10.1080/00325481.2017.1345282 | s2cid = 46184629 }}</ref><ref name="pmid28948482">{{cite journal | vauthors = Bond M, Rabinovich-Guilatt L, Selim S, Darwish M, Tracewell W, Robertson P, Yang R, Malamut R, Colucci P, Ducharme MP, Spiegelstein O | title = Effect of Food on the Pharmacokinetics of Single- and Multiple-Dose Hydrocodone Extended Release in Healthy Subjects | journal = Clinical Drug Investigation | volume = 37 | issue = 12 | pages = 1153–1163 | date = December 2017 | pmid = 28948482 | doi = 10.1007/s40261-017-0575-3 | s2cid = 32440860 }}</ref><ref name="pmid25653563">{{cite journal | vauthors = Farr SJ, Robinson CY, Rubino CM | title = Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers | journal = Clinical Pharmacology | volume = 7 | issue = | pages = 1–9 | date = 2015 | pmid = 25653563 | pmc = 4307648 | doi = 10.2147/CPAA.S70831 | doi-access = free }}</ref><ref name="pmid26614499">{{cite journal | vauthors = Devarakonda K, Kostenbader K, Giuliani MJ, Young JL | title = Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials | journal = BMC Pharmacology & Toxicology | volume = 16 | issue = | pages = 31 | date = November 2015 | pmid = 26614499 | pmc = 4662814 | doi = 10.1186/s40360-015-0032-y | doi-access = free }}</ref>

====Distribution====
The [[volume of distribution]] of hydrocodone is 3.3 to 4.7&nbsp;L/kg.<ref name="ChabnerLongo2010" /> The [[plasma protein binding]] of hydrocodone is 20 to 50%.<ref name="pmid21785485"/>

====Metabolism====
In the [[liver]], hydrocodone is transformed into several [[metabolite]]s, including [[norhydrocodone]], [[hydromorphone]], [[dihydrocodeine|6α-hydrocodol]] (dihydrocodeine), and [[6β-hydrocodol]].<ref name="Zhou2016">{{cite book| vauthors = Zhou S | chapter = Substrates of Human CYP2D6: Opioids and Opioid Receptor Antagonists |title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism| chapter-url = https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA164|date=6 April 2016|publisher=CRC Press|isbn=978-1-4665-9788-4|pages=164–}}</ref> 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via [[glucuronidation]]).<ref name="FFFLM2007">{{cite book|vauthors=Jenkins AJ|chapter=Pharmacokinetics of Specific Drugs|veditors=Karch SB|title=Pharmacokinetics and Pharmacodynamics of Abused Drugs|chapter-url=https://books.google.com/books?id=9fwUQvF4r-cC&pg=PA56|date=9 October 2007|publisher=CRC Press|isbn=978-1-4200-5460-6|pages=56–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203401/https://books.google.com/books?id=9fwUQvF4r-cC&pg=PA56|url-status=live}}</ref><ref name="DasguptaSepulveda2013">{{cite book| vauthors= Broussard LA | chapter = Challenges in Confirmation Testing for Drugs of Abuse | veditors = Dasgupta A, Sepulveda JL |title=Accurate Results in the Clinical Laboratory: A Guide to Error Detection and Correction| chapter-url = https://books.google.com/books?id=HEBloh3nxiAC&pg=PA239|date=22 January 2013|publisher=Newnes|isbn=978-0-12-415858-0|pages=239–}}</ref> Hydrocodone has a [[biological half-life|terminal half-life]] that averages 3.8&nbsp;hours (range 3.3–4.4&nbsp;hours).<ref name="DavisGlare2005" /><ref name="ElliottSmith2016">{{cite book| vauthors = Elliott JA | chapter = Opioids in the management of acute pain | veditors = Elliott JA, Smith HS |title=Handbook of Acute Pain Management| chapter-url=https://books.google.com/books?id=Em7OBQAAQBAJ&pg=PA79|date=19 April 2016|publisher=CRC Press|isbn=978-1-4665-9635-1|pages=79–}}</ref> The hepatic [[cytochrome P450]] enzyme [[CYP2D6]] converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).<ref name="Zhou2016" /><ref name="DasguptaLangman2012" /> However, extensive and poor [[cytochrome 450]] CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor [[quinidine]] did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance.<ref name="pmid9103485">{{cite journal | vauthors = Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, Sellers EM | title = Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 281 | issue = 1 | pages = 103–108 | date = April 1997 | doi = 10.1016/S0022-3565(24)36599-1 | pmid = 9103485 }}</ref><ref name="pmid16968950">{{cite journal | vauthors = Gardiner SJ, Begg EJ | title = Pharmacogenetics, drug-metabolizing enzymes, and clinical practice | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 521–590 | date = September 2006 | pmid = 16968950 | doi = 10.1124/pr.58.3.6 | s2cid = 25747320 }}</ref> Ultra-rapid CYP2D6 metabolizers (1–2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.<ref name="pmid22205192">{{cite journal | vauthors = Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC | title = Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype | journal = Clinical Pharmacology and Therapeutics | volume = 91 | issue = 2 | pages = 321–326 | date = February 2012 | pmid = 22205192 | pmc = 3289963 | doi = 10.1038/clpt.2011.287 }}</ref>

Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.<ref name="Zhou2016" /> In contrast to hydromorphone, it is described as inactive.<ref name="DasguptaLangman2012">{{cite book|vauthors=Sepulveda JL|chapter=Genetic Aspect of Opiate Metabolism and Addiction|veditors=Dasgupta A, Langman LJ|title=Pharmacogenomics of Alcohol and Drugs of Abuse|chapter-url=https://books.google.com/books?id=AiHaRjs3grYC&pg=PA175|date=23 April 2012|publisher=CRC Press|isbn=978-1-4398-5611-6|pages=175–|access-date=23 September 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112203403/https://books.google.com/books?id=AiHaRjs3grYC&pg=PA175|url-status=live}}</ref> However, norhydrocodone is actually a MOR agonist with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals (likely due to poor [[blood–brain barrier]] and thus [[central nervous system]] penetration).<ref name="NavaniYoburn2013">{{cite journal | vauthors = Navani DM, Yoburn BC | title = In vivo activity of norhydrocodone: an active metabolite of hydrocodone | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 347 | issue = 2 | pages = 497–505 | date = November 2013 | pmid = 23995596 | doi = 10.1124/jpet.113.207548 | s2cid = 31072872 }}</ref> Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.<ref name="pmid20837591">{{cite journal | vauthors = Madadi P, Hildebrandt D, Gong IY, Schwarz UI, Ciszkowski C, Ross CJ, Sistonen J, Carleton BC, Hayden MR, Lauwers AE, Koren G | title = Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions | journal = Pediatrics | volume = 126 | issue = 4 | pages = e986–e989 | date = October 2010 | pmid = 20837591 | doi = 10.1542/peds.2009-1907 | s2cid = 42365304 }}</ref> Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.<ref name="pmid23226064">{{cite journal | vauthors = Vuilleumier PH, Stamer UM, Landau R | title = Pharmacogenomic considerations in opioid analgesia | journal = Pharmacogenomics and Personalized Medicine | volume = 5 | pages = 73–87 | date = 2012 | pmid = 23226064 | pmc = 3513230 | doi = 10.2147/PGPM.S23422 | doi-access = free }}</ref>

====Elimination====
Hydrocodone is [[excretion|excreted]] in [[urine]], mainly in the form of [[conjugation (biochemistry)|conjugate]]s.<ref name="Bluth2016" /><ref name="Smith2013" />