2.2 Pharmacokinetics
Systemically administered ketamine is chiefly metabolized by the cytochrome P450 liver enzymes, initially to a much less potent norketamine, and further to inactive hydroxynorketamines, dehydronorketamines, and other metabolites.27,28Ketamine has a relatively low plasma protein binding (10-50%) and is rapidly accumulated in the brain. It has a high clearance rate, with a half-life of 2-4 hours.29,30 The excretion is predominantly in urine, with minimal amounts (<5%) in feces. The rate of elimination of ketamine is twice as rapid in children when compared to adults, likely due to faster enzymatic metabolism in children.31 This information plays a role in determining the ketamine dosing frequency in children. Ketamine is commonly available as a mixture of (S)- and (R)- enantiomers. (S)-enantiomer is more potent as compared to (R)-enantiomer, with some evidence of a more favorable safety profile.32
Due to its metabolism by cytochrome P450 enzymes, there is a potential for drug interactions when used along with enzyme-inducer and enzyme-inhibitor drugs. Drugs like metoclopramide and fosaprepitant, which may at times be used in cancer patients as antiemetics, may have drug interactions with ketamine, and caution must be exercised during their concomitant use. Similarly, other CYP3A4 inhibitors like clarithromycin, azole antifungals, verapamil, and inducers like phenytoin, rifampicin, and steroids can alter ketamine levels.33