title: Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.
abstract: OBJECTIVE
  γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as a recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans.
  
  
  METHODS
  Two oral doses of GHB (25 and 35 mg kg(-1) ) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design.
  
  
  RESULTS
  Maximal concentrations of GHB were (geometric mean and 95% CI): 218 (176-270) nmol ml(-1) and 453 (374-549) nmol ml(-1) for the 25 and 35 mg kg(-1) GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95% CI) were 15 747 (12 854-19 290) and 40 113 (33 093-48 622) nmol∙min ml(-1) for the 20 and 35 mg kg(-1) GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance).
  
  
  CONCLUSIONS
  Evidence was found of a nonlinear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Βasel, CH-4031, Switzerland.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, Zurich, CH-8032, Switzerland.
authors.forename: Boris B
authors.initials: BB
authors.lastname: Quednow
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Βasel, CH-4031, Switzerland.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Liakoni
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, Zurich, CH-8032, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Dornbierer
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, Zurich, CH-8032, Switzerland.
authors.forename: Robin
authors.initials: R
authors.lastname: von Rotz
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern, CH-3012, Switzerland.
authors.forename: Maria Salomé
authors.initials: MS
authors.lastname: Gachet
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern, CH-3012, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, Zurich, CH-8032, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, Zurich, CH-8032, Switzerland.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Bosch
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018755:GABA Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009290:Narcolepsy / Q000188:drug therapy*; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012978:Sodium Oxybate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D018755:GABA Agonists; D006993:Hypnotics and Sedatives; D011619:Psychotropic Drugs; D012978:Sodium Oxybate
keywords: GHB; liquid ecstasy; pharmacokinetic; sodium oxybate