title: Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Zhao
authors.forename: Swarajya Lakshmi Vattem
authors.initials: SL
authors.lastname: Venkata
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Dave A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Brutsche
authors.forename: Lobna
authors.initials: L
authors.lastname: Ibrahim
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000328:Adult; D000465:Algorithms; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007263:Infusions, Parenteral; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine; C050654:6-hydroxynorketamine; C053741:6-hydroxyketamine; C033419:norketamine