Editing Ketamine (section)

=== Pharmacokinetics ===
Ketamine can be absorbed by many different routes due to both its water and lipid solubility. [[Intravenous]] ketamine [[bioavailability]] is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%,<ref name="MathewZarate2016" /> and [[epidural]] bioavailability is 77%.<ref name="Kintz2014" /> Subcutaneous bioavailability has never been measured but is presumed to be high.<ref name="Mao2016">{{cite book | vauthors = Mao J |title=Opioid-Induced Hyperalgesia |url=https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127|date=19 April 2016 |publisher=CRC Press |isbn=978-1-4200-8900-4 |pages=127– |url-status=live |archive-url=https://web.archive.org/web/20170908185726/https://books.google.com/books?id=_VrvBQAAQBAJ&pg=PA127 |archive-date=8 September 2017 }}</ref> Among the less invasive routes, the intranasal route has the highest bioavailability (45–50%)<ref name="MathewZarate2016" /><ref name="pmid23521979" /> and oral&nbsp;– the lowest (16–20%).<ref name="MathewZarate2016" /><ref name="pmid23521979" /> Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.<ref name="MathewZarate2016" /><ref name="Hashimoto2019" /><ref name="pmid23521979" />

After absorption ketamine is rapidly [[distribution (pharmacology)|distributed]] into the brain and other tissues.<ref name="pmid27028535" /> The [[plasma protein binding]] of ketamine is variable at 23–47%.<ref name="pmid6884418" />

[[File:Ketamine metabolites2.png|class=skin-invert-image|thumb|upright=1.7|Major routes of ketamine metabolism<ref name="pmid29945898" />]]
In the body, ketamine undergoes extensive [[metabolism]]. It is [[biotransformation|biotransformed]] by [[CYP3A4]] and [[CYP2B6]] [[isoenzyme]]s into [[norketamine]], which, in turn, is converted by [[CYP2A6]] and CYP2B6 into [[hydroxynorketamine]] and [[dehydronorketamine]].<ref name="pmid29945898" /> Low oral bioavailability of ketamine is due to the [[first-pass effect]] and, possibly, ketamine intestinal metabolism by CYP3A4.<ref name="pmid27763887" /> As a result, norketamine plasma levels are several-fold higher than ketamine following oral administration, and norketamine may play a role in anesthetic and analgesic action of oral ketamine.<ref name="MathewZarate2016" /><ref name="pmid27763887">{{cite journal |vauthors=Rao LK, Flaker AM, Friedel CC, Kharasch ED |title=Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance |journal=Anesthesiology |volume=125 |issue=6 |pages=1103–1112 |date=December 2016 |pmid=27763887 |doi=10.1097/ALN.0000000000001392 |s2cid=41380105 }}</ref> This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.<ref name="pmid27763887" /><ref name="pmid25702819">{{cite journal |vauthors=Li Y, Jackson KA, Slon B, Hardy JR, Franco M, William L, Poon P, Coller JK, Hutchinson MR, Currow DC, Somogyi AA |title=CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects |journal=Br J Clin Pharmacol |volume=80 |issue=2 |pages=276–84 |date=August 2015 |pmid=25702819 |pmc=4541975 |doi=10.1111/bcp.12614 }}</ref>

After an intravenous injection of [[tritium]]-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from feces.<ref name="pmid4603048">{{cite journal |vauthors=Chang T, Glazko AJ |title=Biotransformation and disposition of ketamine |journal=Int Anesthesiol Clin |volume=12 |issue=2 |pages=157–77 |date=1974 |pmid=4603048 |doi=10.1097/00004311-197412020-00018 |s2cid=30723730 }}</ref> The medication is excreted mostly in the form of [[metabolite]]s, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.<ref name="pmid20693870" />