Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects.

Liechti, Matthias E; Quednow, Boris B; Liakoni, Evangelia; Dornbierer, Dario; von Rotz, Robin; Gachet Otanez, Maria Salomé; Gertsch, Jürg; Seifritz, Erich; Bosch, Oliver G (2015). Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects. British journal of clinical pharmacology, 81(5), pp. 980-988. Wiley-Blackwell 10.1111/bcp.12863

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AIMS γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship 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) 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 and 453 (374-549) nmol/ml for the 25 and 35 mg/kg 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 for the 20 and 35 mg/kg 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). CONCLUSION Evidence was found of a non-linear 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. This article is protected by copyright. All rights reserved.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gachet Otanez, Maria Salomé and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0306-5251

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Feb 2016 10:46

Last Modified:

01 Mar 2017 02:30

Publisher DOI:

10.1111/bcp.12863

PubMed ID:

26659543

Uncontrolled Keywords:

GHB; liquid ecstasy; pharmacokinetic; sodium oxybate

BORIS DOI:

10.7892/boris.75956

URI:

https://boris.unibe.ch/id/eprint/75956

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