Background

The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine.

Methods

Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis.

Results

After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations–time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers.

Conclusions

Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion.

Editor’s Perspective
What We Already Know about This Topic
  • Ketamine produces anesthesia and analgesia with psychoactive side effects

  • Norketamine, its primary metabolite, is oxidized to 2R,6R- and 2S,6S-hydroxynorketamine, which may have analgesic and antidepressant activity without adverse psychoactive effects

  • Systemic exposure to the 2,6-hydroxynorketamines is three times more than to ketamine after intravenous infusion and five times more than to ketamine after drinking a ketamine solution

What This Article Tells Us That Is New
  • The hypothesis that systemic exposure to the 2,6-hydroxynorketamines can be increased by administration of a prolonged-release ketamine dosage form was tested in a controlled, five-period, ascending-dose pharmacokinetic study in 15 healthy volunteers

  • The (mean ± SD) oral bioavailabilities of S- and R-ketamine were 15 ± 8% and 19 ± 10%, respectively

  • The systemic exposure to the hydroxynorketamine stereoisomers after oral administration of 40 mg of prolonged-release ketamine was 10 to 11 times that after administration of a comparable intravenous dose (5 mg)

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