Therapeutic potential of monocarboxylate transporter inhibition for the treatment of GHB overdose
Morse, Bridget L.
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Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (BD), have recently become known as popular drugs of abuse in several countries worldwide. Despite manifestations of GHB overdose including coma, respiratory depression and death, there currently exists no effective treatment for GHB intoxication. In vitro and in vivo studies have confirmed the role of monocarboxylate transporters (MCTs) the renal reabsorption of GHB, and that administration of MCT inhibitors increases GHB renal and total clearance, making MCT inhibition a potential therapeutic strategy in GHB overdose. While previous studies have established the ability of intravenously administered MCT inhibitors to increase the clearance of intravenously administered GHB in rats, the purpose of the current research was to apply this concept to conditions applicable to clinical GHB intoxication. Using therapeutic dosages of GHB, a clinical study was performed to assess the effect of the MCT inhibitor L-lactate on GHB pharmacokinetics, and this study demonstrated L-lactate administration increases the renal clearance of GHB in humans. The low dose used in this study limited evaluation of effects on total clearance as renal clearance is negligible at low GHB doses. Rat studies were utilized to assess the effect of L-lactate on GHB toxicokinetics/toxicodynamics, using the clinically relevant endpoint of respiratory depression, under clinically relevant conditions of ethanol co-administration and oral GHB/GBL overdose. A pilot study assessing GHB-induced respiratory depression indicated the primary effect of GHB on respiration to be a decrease in respiratory rate, and that this decrease could be completely inhibited by GABA B receptor inhibition. In this study, treatment with both L-lactate and GABA B receptor antagonists significantly improved GHB-induced respiratory depression, and the benefit of combined receptor-transporter inhibition therapy was demonstrated. In an evaluation of the toxicokinetic/toxicodynamic interactions between GHB and ethanol, we found that ethanol potentiated GHB sedative effect and GHB-induced respiratory depression and increased the risk of death in GHB overdose. Both L-lactate and GABA B receptor antagonists were effective at preventing fatality secondary to respiratory arrest in GHB-ethanol intoxication, similar to that of GHB alone. GHB and GBL are abused solely by oral ingestion, and MCTs also have a proposed role in the absorption of GHB. In a study evaluating effects of L-lactate on oral GHB/GBL toxicokinetics, administration of IV L-lactate with low oral doses of GHB and GBL resulted in similar effects as our clinical study. However, L-lactate administration with high oral doses of GHB and GBL resulted in increased renal, nonrenal, and total oral clearance. Increased oral clearance in the absence of increased renal clearance at a very high oral dose of GHB suggests effects of IV L-lactate on GHB absorption. IV L-lactate improved respiratory depression following GHB overdose and completely prevented mortality following a fatal oral dose of GBL. Blood:plasma partitioning of GHB was assessed in vitro and in vivo, in the presence and absence of L-lactate, to determine effects of L-lactate on GHB distribution. In vivo studies demonstrated linear blood:plasma partitioning of GHB, and no effect of L-lactate on this partitioning, even though L-lactate increased GHB renal clearance in the same animals. In vitro studies explained these findings, demonstrating a large increase in the K m value for GHB MCT-mediated transport at blood pH compared to that in the renal tubule. Finally, mechanistic toxicokinetic/toxicodynamic modeling was performed to characterize GHB toxicokinetics/toxicodynamics and interactions with L-lactate. This model incorporated multiple MCT-mediated processes for both GHB and L-lactate and was able to capture changes in both GHB and L-lactate toxicokinetics with concomitant drug administration, as well as effects on respiration. In conclusion, through evaluation at low GHB doses in humans and under clinical overdose conditions in rats, the current research supports MCT inhibition with L-lactate as a treatment strategy for GHB intoxication, and its further evaluation in clinical GHB overdose.