Editing Hydrocodone (section)

====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 | display-authors = 6 | 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 | display-authors = 6 | 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>