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 rat… Show more
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Purpose
Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).
Methods
Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 hours. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.
Results
AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).
Conclusion
The novel and highly potent MCT inhibitor represents a potential treatment option for GHB 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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Purpose
Monocarboxylate transporter (MCT) inhibition represents a potential treatment strategy for γ-hydroxybutyric acid (GHB) overdose by blocking its renal reabsorption in the kidney. This study further evaluated the effects of a novel, highly potent MCT inhibitor, AR-C155858, on GHB toxicokinetics/toxicodynamics (TK/TD).
Methods
Rats were administered GHB (200, 600 or 1500 mg/kg i.v. or 1500 mg/kg po) with and without AR-C155858. Breathing frequency was continuously monitored using whole-body plethysmography. Plasma and urine samples were collected up to 8 hours. The effect of AR-C155858 on GHB brain/plasma partitioning was also assessed.
Results
AR-C155858 treatment significantly increased GHB renal and total clearance after intravenous GHB administration at all the GHB doses used in this study. GHB-induced respiratory depression was significantly improved by AR-C155858 as demonstrated by an improvement in the respiratory rate. AR-C155858 treatment also resulted in a significant reduction in brain/plasma partitioning of GHB (0.1 ± 0.03) when compared to GHB alone (0.25 ± 0.02). GHB CLR and CLoral (CL/F) following oral administration were also significantly increased following AR-C155858 treatment (from 1.82 ± 0.63 to 5.74 ± 0.86 and 6.52 ± 0.88 to 10.2 ± 0.75 ml/min/kg, respectively).
Conclusion
The novel and highly potent MCT inhibitor represents a potential treatment option for GHB overdose.
“…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.…”
Section: Mcts In Drug Dispositionmentioning
confidence: 97%
“…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]. …”
Section: Mcts In Drug Dispositionmentioning
confidence: 99%
“…of three experiments, each experiment performed in triplicate. (Figure taken from Roiko et al 2012 with permission) [116]. …”
Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. Currently, fourteen members of this transporter family have been identified by sequence homology, of which only the first four members (MCT1- MCT4) have been shown to mediate the proton-linked transport of monocarboxylates. Another transporter family involved in the transport of endogenous monocarboxylates is the sodium coupled MCTs (SMCTs). These act as a symporter and are dependent on a sodium gradient for their functional activity. MCT1 is the predominant transporter among the MCT isoforms and is present in almost all tissues including kidney, intestine, liver, heart, skeletal muscle and brain. The various isoforms differ in terms of their substrate specificity and tissue localization. Due to the expression of these transporters in the kidney, intestine, and brain, they may play an important role in influencing drug disposition. Apart from endogenous short chain monocarboxylates, they also mediate the transport of exogenous drugs such as salicylic acid, valproic acid, and simvastatin acid. The influence of MCTs on drug pharmacokinetics has been extensively studied for γ-hydroxybutyrate (GHB) including distribution of this drug of abuse into the brain and the results will be summarized in this review. The physiological role of these transporters in the brain and their specific cellular localization within the brain will also be discussed. This review will also focus on utilization of MCTs as potential targets for drug delivery into the brain including their role in the treatment of malignant brain tumors.
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