title: S-ketamine concentrations are greatly increased by grapefruit juice.
abstract: OBJECTIVE
  We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine.
  
  
  METHODS
  A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters.
  
  
  RESULTS
  Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve(AUC0-∞) by 3.0-fold (range 2.4- to 3.6-fold; P<0.001), the peak plasma concentration (Cmax) by 2.1-fold (range 1.8- to 2.6-fold; P<0.001), and the elimination half-life by 24% (P<0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUCm/AUCp) was decreased by 57% (P<0.001) during the grapefruit phase.Self-rated relaxation was decreased (P<0.05) and the performance in the digit symbol substitution test was increased (P<0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected.
  
  
  CONCLUSIONS
  Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers.Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice.
authors.affiliation: Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
authors.forename: Marko A
authors.initials: MA
authors.lastname: Peltoniemi
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001628:Beverages; D032083:Citrus paradisi; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D055815:Young Adult
chemical_list: D007649:Ketamine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C033419:norketamine