ORIGINAL ARTICLE Disposition of Gamma-Hydroxybutyric Acid in Conventional and Nonconventional Biologic Fluids After Single Drug Administration: Issues in Methodology and Drug Monitoring Sergio Abanades,*‡ Magi Farre ´,*‡ Mireia Segura,*§ Simona Pichini,† Antoni Pastor,* Roberta Pacifici,† Manuela Pellegrini,† and Rafael de la Torre*§ Abstract: Little controlled drug administration data are available to aid in the interpretation of gamma-hydroxybutyric acid (GHB) distribution in conventional and nonconventional fluids and the potential correlation between the pharmacokinetics of GHB and drug effects. Single oral sodium GHB doses of 50 mg/kg were admin- istered to five volunteers. Plasma, oral fluid, urine, and sweat were analyzed for GHB by gas chromatography–mass spectrometry. GHB stability in plasma was studied at different storage temperatures. Subjective effects were measured using a set of 13 different visual analog scales. Mean peak GHB plasma concentrations at 30 minutes were 83.1 mg/mL. After the absorption phase, concentrations declined to mean values of 0.9 mg/mL at 6 hours. GHB was found in oral fluid at peak value concentrations equivalent to one third to one fourth of those found in plasma. The oral fluid-to-plasma ratio varied two fold in the 1- to 6-hour time range but alwayswas lower than unit. The mean half-life (t 1/2 ) of GHB was approximately 0.7 hour in plasma and approximately 1.2 hours in oral fluid. GHB urinary excretion is less than 2% of the dose administered. GHB was also detected in sweat at low concentrations. GHB showed a mixed sedative–stimulant pattern with subjective effects peaking between 1 and 1.5 hours after drug administration and lasting for 2 hours. Oral fluid and sweat appeared not to be suitable biologic matrices for monitoring GHB consumption. GHB -mediated subjective effects are related to GHB plasma concentrations. Key Words: GHB, plasma, oral fluid, subjective effects, sweat (Ther Drug Monit 2007;29:64–70) INTRODUCTION Gamma-hydroxybutyric acid (GHB, ‘‘liquid ecstasy,’’ gamma-hydroxybutyrate, 4-hydroxybutiric acid, 4-hydroxy- butanoic acid, oxybate) is a short chain fatty acid. It is an endogenous metabolite and a precursor of the neurotransmitter gamma-aminobutyric acid. GHB can be formed in human peripheral tissues from two precursors, gamma-butyrolactone and 1,4-butanediol (Fig. 1) and acts in the central nervous system as a neuromodulator. 1 GHB is marketed in the United States under the name Xyrem for the treatment of cataplexy in patients with narcolepsy and in some European countries as an anesthetic agent and for the treatment of alcohol withdrawal (eg, Alcover in Italy). GHB has also emerged as a major recreational drug and health problem all over the world. By the late 1990s, GHB had become a popular drug used in clubs and gained significant notoriety as a major drug of abuse and as a date rape drug. Gamma-butyrolactone and 1,4-butanediol, both GHB metabolic precursors, have also been abused in humans. During the last years, it has become a major concern in emergency departments of some countries as a result of an important increase in the number of cases of intoxication. GHB overdose frequently results in nonreactive coma associated with bradycardia, hypothermia, agitated delirium, myoclonus, and rarely seizure-like activity. 2 Although GHB has been successfully detected in urine and blood of consumers, 3–12 drug measurement in biologic fluids to assess both voluntary and involuntary consumption has some drawbacks. First, GHB is eliminated from the body rapidly, making identification dependent on the time elapsed between consumption and biologic matrix collection. This fact addressed investigations toward the use of biologic matrices with time windows for drug detection wider than blood and urine such as hair. 13,14 Second, a compounding difficulty resides in the fact that GHB is an endogenous compound present in the human body with measurable baseline con- centrations both in blood and urine. 15–18 Hence, different authors proposed cutoff (ie, 10 mg/mL for urine samples) concentrations to identify exogenous GHB exposure. 15,16,19 Received for publication April 27, 2006; accepted October 19, 2006. From the *Pharmacology Research Unit, Human Pharmacology and Clinical Neurosciences Research Group. Institut Municipal d’Investigacio ´ Me `dica (IMIM), Barcelona, Spain; †Drug Research and Evaluation Department, Istituto Superiore di Sanita `, Roma, Italy; ‡Universitat Auto `noma de Barcelona, Barcelona, Spain; and §Universitat Pompeu Fabra, Barcelona, Spain. Supported in part by grants from Fondo de Investigacio ´n Sanitaria FIS (02/0824, Red de Trastornos Adictivos G03/005, Red CIEN, C03/06), Generalitat de Catalunya (CIRIT 2001SGR00407), and Istituto Superiore di Sanita `, Rome, Italy (funded by the Dipartimento Nazionale per le politiche antidroga della Presidenza del Consiglio dei Ministri). Sergio Abanades is the recipient of a fellowship from the Spanish Health Authorities, (Ayudas para contratar profesionales sanitarios que hayan finalizado el perı ´odo de Formacio ´ n Sanitaria Especializada. Instituto Carlos III (CM04/00216). Correspondence: Pharmacology Research Unit, Human Pharmacology and Clinical Neurosciences Research Group Institut Municipal d’Investigacio ´ Me `dica (IMIM) c/Doctor Aiguader 80, 08003 Barcelona, Spain (e-mail: rtorre@imim.es). Copyright Ó 2007 by Lippincott Williams & Wilkins 64 Ther Drug Monit  Volume 29, Number 1, February 2007