Editing Methadone (section)

=== Metabolism ===
Methadone has a slow metabolism and very high [[Lipophilicity|fat solubility]], making it longer lasting than morphine-based drugs. Methadone has a typical elimination [[half-life]] of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,<ref name="Kell">{{cite journal | vauthors = Kell MJ | title = Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting | journal = Journal of Addictive Diseases | volume = 13 | issue = 1 | pages = 5–26 | year = 1994 | pmid = 8018740 | doi = 10.1300/J069v13n01_02 }}</ref><ref name=Europad>{{cite journal | vauthors = Eap CB, Déglon JJ, Baumann P |title=Pharmacokinetics and pharmacogenetics of methadone: Clinical relevance |journal=Heroin Addiction and Related Clinical Problems |volume=1 |issue=1 |pages=19–34 |year=1999 |url=http://atforum.com/pdf/europad/HeroinAdd1-1.pdf#page=25}}</ref> ranging from as few as 4 hours to as many as 130 hours,<ref name="EapI">{{cite journal | vauthors = Eap CB, Buclin T, Baumann P | title = Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence | journal = Clinical Pharmacokinetics | volume = 41 | issue = 14 | pages = 1153–1193 | year = 2002 | pmid = 12405865 | doi = 10.2165/00003088-200241140-00003 | s2cid = 1396257 }}</ref> or even 190 hours.<ref>{{cite journal | vauthors = Manfredonia JF | title = Prescribing methadone for pain management in end-of-life care | journal = The Journal of the American Osteopathic Association | volume = 105 | issue = 3 Suppl 1 | pages = S18–S21 | date = March 2005 | pmid = 18154194 | url = http://www.jaoa.org/cgi/content/full/105/3_suppl/18S | url-status = dead | archive-url = https://web.archive.org/web/20070520062222/http://www.jaoa.org/cgi/content/full/105/3_suppl/18S | archive-date = 20 May 2007 }}</ref> This variability is apparently due to genetic variability in the production of the associated cytochrome enzymes [[CYP3A4]], [[CYP2B6]] and [[CYP2D6]]. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in opioid [[Drug detoxification|withdrawal management]] and maintenance programs. People who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.<ref name="EapI"/> This can also allow lower total doses in some such people. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day normally dividing daily dosage for administration at 8-hour intervals.<ref>Medscape Methadone Dosage. [https://reference.medscape.com/drug/methadose-dolophine-methadone-343317].</ref>

The main metabolic pathway involves ''N''-demethylation by CYP3A4 in the liver and intestine to give [[2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine]] (EDDP).<ref name=acta08/><ref>{{cite journal | vauthors = Preston KL, Epstein DH, Davoudzadeh D, Huestis MA | title = Methadone and metabolite urine concentrations in patients maintained on methadone | journal = Journal of Analytical Toxicology | volume = 27 | issue = 6 | pages = 332–341 | date = September 2003 | pmid = 14516485 | doi = 10.1093/jat/27.6.332 | doi-access = free | title-link = doi }}</ref> This inactive product, as well as the inactive 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP), produced by a second ''N''-demethylation, are detectable in the urine of those taking methadone.
<div class="skin-invert-image"><gallery caption="Methadone and its two main metabolites" perrow="3">
File:Methadone.svg|Methadone
File:EDDP.png|EDDP
File:EDMP.png|EDMP
</gallery></div>