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

Abstract

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.

A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose

“…Previous reports have demonstrated that the sedative and hypnotic effects of GHB correlate with its brain concentrations (24, 30). Therefore, our results suggest that the respiratory effects of GHB also correlate with its concentration in the brain and needs to be confirmed in future studies by measuring GHB brain ECF concentrations in the presence of AR-C155858.…”

“…There is currently no approved treatment strategy for GHB overdose. GHB is a substrate for MCT1, a transporter with ubiquitous distribution in the body and responsible for its oral absorption, renal reabsorption and transport across the BBB (8, 9, 11, 24). GHB has also been shown to be a substrate for SMCT1 in rat thyroid follicular cells (16), however, the importance of SMCT1 in the renal reabsorption of GHB is not yet completely understood.…”

Role of Monocarboxylate Transporters in Drug Delivery to the Brain

“…4B). The uptake of GHB into these cell lines was found to be significantly inhibited by CHC [116]. These data suggest the involvement of MCTs in GHB uptake into the brain.…”

“…However, the overall partition coefficient of GHB into the brain was not significantly different at the doses studied which suggested that the distribution of GHB into brain was not capacity limited at the doses studied. Although, based on the K m values that were obtained, the distribution of GHB into the brain could be saturated at higher concentrations such as those observed in overdose situations [116]. …”

“…of three experiments, each experiment performed in triplicate. (Figure taken from Roiko et al 2012 with permission) [116]. …”