Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons

Abstract

Rationale Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are prodrugs for gamma-hydroxybutyrate (GHB). Like GHB, GBL and 1,4-BD are drugs of abuse, but their behavioral effects may differ from GHB under some conditions. Objectives The first study compared the behavioral effects of GBL (32−240 mg/kg) and 1,4-BD (32−240 mg/kg) with each other and to effects previously reported for GHB (32−420 mg/kg). A second study determined GHB pharmacokinetics following intragastric administration of GHB, GBL, and 1,4-BD. Methods Operant responding for food, observed behavioral effects, and a fine-motor task occurred at multiple time intervals after administration of drug or vehicle. In a separate pharmacokinetics study, blood samples were collected across multiple time points after administration of GHB, GBL, and 1,4-BD. Results Like GHB, GBL, and 1,4-BD impaired performance on the fine-motor task, but the onset of motor impairment differed across drugs. GBL and 1,4-BD dose dependently decreased the number of food pellets earned, but at lower doses than previously observed for GHB. Similar to GHB, both GBL and 1,4-BD produced sedation, muscle relaxation, gastrointestinal symptoms, and tremors/jerks. Administration of GBL and 1,4-BD produced higher maximum concentrations of GHB with shorter times to maximum concentrations of GHB in plasma when compared to GHB administration. Conclusions GBL and 1,4-BD produced behavioral effects similar to those previously reported with GHB and the time course of effects were related to blood levels of GHB. Given their higher potency and faster onset of effects, the abuse liability of GBL and 1,4-BD may be greater than GHB.

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

“…Our data are also consistent with previous studies in rats demonstrating much higher plasma concentrations of GHB after GBL administration compared with administration of equimolar doses of GHB itself (Lettieri and Fung, 1978). Although toxicokinetic data are not available for comparison in humans, similar data have been reported in nonhuman primates (Goodwin et al, 2009). We additionally report that, similar to GHB administration, renal clearance significantly contributes to total GHB elimination after a high GBL dose.…”

“…Additionally, reports indicate that abuse of the GHB precursor g-butyrolactone (GBL) may be increasing in the United States and other countries due to the classification of GHB as a controlled substance (Wood et al, 2011). GBL is rapidly converted to GHB by lactonases present in blood (Giarman and Roth, 1964), and studies have suggested that, compared with GHB, GBL is more rapidly absorbed after oral administration (Root, 1965;Lettieri and Fung, 1976;Goodwin et al, 2009), potentially making GBL abuse particularly dangerous. Overdose of GHB and GBL remains a significant concern, as it results in coma, respiratory depression, and fatalities, but there exists no specific treatment of GHB intoxication.…”

Concentration-Effect Relationships for the Drug of Abuse γ-Hydroxybutyric Acid

“…In addition, brain GHB concentrations have been reported to parallel plasma concentrations and show similar relationships with offset of sedative/hypnotic effect (Snead et al, 1976;Snead, 1978). The relationship between plasma and brain GHB concentrations (and total exposure) is not limited to the sedative/hypnotic effect; literature reports have illustrated exposure-and concentration-effect for electroencephalographic effects (Snead et al, 1976;Snead, 1978Snead, , 1991, time to complete fine motor task (Goodwin et al, 2009), and ataxia (Goodwin et al, 2009). Interestingly, GHB exhibits complex dose-response relationships with body temperature, suggesting there are multiple pathways contributing to the observed toxicological effects of GHB (Snead, 1990).…”

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

“…When given exogenously, GHB readily crosses the blood-brain barrier and produces a number of unusual behavioral, electrophysiological, and biochemical outcomes, in addition to absence seizures (178,179,197,198). Depending upon the dose administered, these effects include short-term amnesia and memory loss at low dose, seizure, or paradoxical sleep induction at moderate dosage, and stupor, coma, and potentially respiratory arrest at very high dosages (72,75,179). GHB was initially developed as a GABA-analog with potential anesthetic properties (and is still used in this mode today), but early testing in rat and primates led to movement abnormalities and disturbances of the electroencephalogram (EEG) (177).…”