Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression

Br J Clin Pharmacol. 2012 Aug;74(2):304-14. doi: 10.1111/j.1365-2125.2012.04198.x.


Aim: To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant bipolar depression.

Method: Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK, (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two-stage algorithm in ADAPT5.

Results: Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter-patient variations in terminal half-lives and relative metabolite concentrations; at 230 min (R,S)-DHNK was the major metabolite in four out of nine patients, (R,S)-norKet in three out of nine patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates.

Conclusion: This represents the first PK analysis of (2S,6S;2R,6R)-HNK and (R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Algorithms
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / blood
  • Antidepressive Agents / pharmacokinetics*
  • Biotransformation
  • Bipolar Disorder / blood
  • Bipolar Disorder / drug therapy*
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Resistance*
  • Female
  • Humans
  • Hydroxylation
  • Infusions, Parenteral
  • Ketamine / administration & dosage
  • Ketamine / analogs & derivatives
  • Ketamine / blood
  • Ketamine / pharmacokinetics*
  • Male
  • Middle Aged
  • Models, Biological*
  • Young Adult


  • Antidepressive Agents
  • Ketamine
  • 6-hydroxynorketamine
  • 6-hydroxyketamine
  • norketamine