Pharmacokinetics
Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility. When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine. Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine. As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration. Bioavailability through the oral route reaches 17-20%; bioavailability through other routes are as follows: 93% intramuscularly, 25-50% intranasally, 30% sublingually, and 30% rectally. Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally. Ketamine's duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours orally.
Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.
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