Case series of 226 γ-hydroxybutyrate–associated deaths: lethal toxicity and trauma

Zvosec, Deborah L.; Smith, Stephen W.; Porrata, Trinka; Strobl, A. Quinn; Dyer, Jo Ellen

doi:10.1016/j.ajem.2009.11.008

Cited by 121 publications

(130 citation statements)

References 69 publications

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“…From 30 to 180 min, GHB plasma concentrations ranged from 1020 to 357 g/ml (9.8 -3.4 mM), 793 to 249 g/ml (7.6 -2.4 mM), and 569 to 69 g/ml (5.5-0.6 mM) for the 800, 600, and 400 mg/kg doses, respectively. Post-mortem GHB plasma concentrations were recently reported to be 18 to 4400 mg/l, or 172 M to 42.2 mM (Zvosec et al, 2011), indicating that the GHB doses used here elicit plasma GHB concentrations that are relevant to concentrations of GHB observed in clinical cases. These data, in conjunction with the dose-normalized ECF concentration-time profiles, the partitioning time course of brain ECF to plasma, and estimated K m values from in vitro uptake studies, suggest that the distribution of GHB into the brain is saturated only at very high plasma concentrations such as those seen after toxic doses of GHB [up to 21 mM (Knudsen et al, 2010) or 42 mM (Zvosec et al, 2011)].…”

Section: Brain Uptake Of Ghbmentioning

confidence: 97%

Brain Uptake of the Drug of Abuse γ-Hydroxybutyric Acid in Rats

Roiko

Felmlee²,

Morris³

2011

Drug Metab Dispos

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ABSTRACT:␥-Hydroxybutyric acid (GHB) is an endogenous compound and a substrate for the ubiquitous monocarboxylate transporter (MCT) family. GHB is also a drug of abuse due to its sedative/hypnotic and euphoric effects, with overdoses resulting in toxicity and death. The goal of this study was to characterize the distribution of GHB into the brain using in vivo microdialysis and in vitro uptake studies and to determine concentration-effect relationships for GHB in a rat animal model. GHB was administered to rats (400, 600, and 800 mg/kg i.v.), and blood, dialysate, and urine were collected for 6 h post-GHB administration. The GHB plasma and extracellular fluid (ECF) concentration-time profiles revealed that GHB concentrations in ECF closely followed plasma GHB concentrations. Sleep time increased in a dosedependent manner (91 ؎ 18, 134 ؎ 11, and 168 ؎ 13 min, for GHB 400, 600, and 800 mg/kg, respectively). GHB partitioning into brain ECF was not significantly different at 400, 600, and 800 mg/kg. GHB uptake in rat and human brain endothelial cells exhibited concentration dependence. The concentrationdependent uptake of GHB at pH 7.4 was best-fit to a singletransporter model [K m ‫؍‬ 18.1 mM (human), 23.3 mM (rat), V max ‫؍‬ 248 and 258 pmol ⅐ mg ؊1 ⅐ min ؊1 for human and rat, respectively].These findings indicate that although GHB distribution into the brain is mediated via MCT transporters, it is not capacity-limited over the range of doses studied in this investigation.

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Section: Brain Uptake Of Ghbmentioning

confidence: 97%

Brain Uptake of the Drug of Abuse γ-Hydroxybutyric Acid in Rats

Roiko

Felmlee²,

Morris³

2011

Drug Metab Dispos

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“…[18,19] However, there has been little systematic investigation of the incidence of GHB- likely underestimates the number of deaths due to the fact that GHB analysis is not routinely performed in post-mortem investigations in the UK. [19] As reports suggest that the use of GHB and the incidence of chemsex are increasing, and GHB is the drug most linked to acute harm out of those used in Chemsex, we systematically investigated the numbers of GHB-associated deaths from London Coroners' jurisdictions to see whether there was evidence of increased deaths associated with GHB which suggest increased and/or more dangerous use of the drug.…”

Section: Introductionmentioning

confidence: 99%

An observed rise in γ-hydroxybutyrate-associated deaths in London: Evidence to suggest a possible link with concomitant rise in chemsex

Hockenhull

Murphy

Paterson

2017

Forensic Science International

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“…GHB has also recently been recognized as a common drug of abuse. Overdose cases involving GHB and its precursors, 1,4-butanediol and -butyrolactone, have been reported in the United States and other Western countries and have resulted in GHB-induced coma, respiratory depression, and fatality (Caldicott et al, 2004;Zvosec et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

γ-Hydroxybutyrate Blood/Plasma Partitioning: Effect of Physiologic pH on Transport by Monocarboxylate Transporters

Morse

Felmlee²,

Morris³

2011

Drug Metab Dispos

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ABSTRACT:The drug of abuse ␥-hydroxybutyrate (GHB) displays nonlinear renal clearance, which has been attributed to saturable renal reabsorption by monocarboxylate transporters (MCTs) present in the kidney. MCT1 is also present in red blood cells (RBCs); however, the significance of this transporter on the blood/plasma partitioning of GHB is unknown. The purpose of this research was to characterize the transport of GHB across the RBC membrane and assess GHB blood/plasma partitioning in vivo in the presence and absence of a competitive MCT inhibitor, L-lactate. In vitro experiments were performed using freshly isolated rat erythrocytes at pH values of 6.5 and 7.4. Inhibition with p-chloromercuribenzene sulfonate and 4,4-diisothiocyanostilbene-2,2-disulfonate were used to determine the contribution of MCT1 and band 3, respectively, on GHB uptake. For in vivo experiments, rats were administered GHB (400-1500 mg/kg) with and without L-lactate. In vitro experiments demonstrated that GHB is transported across the RBC membrane primarily by MCT1 at relevant in vivo concentrations. The K m for MCT1 was lower at pH 6.5 than that at pH 7.4, 2.2 versus 17.0 mM, respectively. The in vivo blood/plasma partitioning of GHB displayed linearity across all concentrations. L-Lactate coadministration increased GHB renal clearance but had no effect on the blood/ plasma ratio. Unlike its MCT-mediated transport in the intestine and kidneys, GHB blood/plasma partitioning appears to be linear and is unaffected by L-lactate. These findings can be attributed, at least in part, to differences in physiologic pH at different sites of MCT-mediated transport.

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Case series of 226 γ-hydroxybutyrate–associated deaths: lethal toxicity and trauma

Cited by 121 publications

References 69 publications

Brain Uptake of the Drug of Abuse γ-Hydroxybutyric Acid in Rats

Brain Uptake of the Drug of Abuse γ-Hydroxybutyric Acid in Rats

An observed rise in γ-hydroxybutyrate-associated deaths in London: Evidence to suggest a possible link with concomitant rise in chemsex

γ-Hydroxybutyrate Blood/Plasma Partitioning: Effect of Physiologic pH on Transport by Monocarboxylate Transporters

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