Sublingual and rectal bioavailabilities are intermediate at approximately 25–50%.After absorption ketamine is rapidly distributed into the brain and other tissues. The plasma protein binding of ketamine is variable at 23 to 47%. In the body ketamine undergoes extensive metabolism. It is biotransformed by CYP3A4 and CYP2B6 isoenzymes into norketamine, which, in turn, is converted by CYP2A6 and CYP2B6 into hydroxynorketamine and dehydronorketamine. Low oral bioavailability of ketamine is due to the first-pass effect and, possibly, ketamine intestinal metabolism by CYP3A4. 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. This also explains why oral ketamine levels are independent of CYP2B6 activity, unlike subcutaneous ketamine levels.After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from the feces. The medication is excreted mostly in the form of metabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine. Chemistry
Synthesis
2-chlorobenzonitrile is reacted with the Grignard reagent cyclopentylmagnesium bromide to give (2-chlorophenyl)(cyclopentyl)methanone. This is then brominated using bromine to form the corresponding bromoketone, which is then reacted with methylamine in an aqueous solution to form the methylimino derivative, 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol, with hydrolysis of the tertiary bromine atom. This final intermediate is then heated in decalin or another suitable high-boiling solvent, upon which a ring-expansion rearrangement occurs, forming ketamine. Structure
In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound.
Some daily users reported withdrawal symptoms, primarily anxiety, shaking, sweating, and palpitations, following the attempts to stop. Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine. Interactions
Ketamine potentiates the sedative effects of propofol and  midazolam. Naltrexone potentiates psychotomimetic effects of a low dose of ketamine, while lamotrigine and nimodipine decrease them. Clonidine reduces the increase of salivation, heart-rate and blood-pressure during ketamine anesthesia and decreases the incidence of nightmares.Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine. It appears most conventional antidepressants can be safely combined with ketamine. Pharmacology
Pharmacodynamics
Mechanism of action
Antagonism of the NMDA receptor is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine. NMDA receptor antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamines actions interfere with pain transmission in the spinal cord.The mechanism of action of ketamine in alleviating depression is not well understood, and is an area of active investigation. Possible mechanisms include direct action on the NMDA receptor, downstream effects on regulators such as BDNF and mTOR, and effects of ketamines metabolites such as hydroxynorketamine. It is not clear whether NMDA receptor is solely responsible for this action or interactions with other receptors are also necessary. It is not also not clear whether ketamine alone is sufficient for the antidepressive action or its metabolites also are important.