Club Drug Interactions: Toxicokinetics/Toxicodynamics and Treatment Strategies
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γ-hydroxybutyric acid (GHB), a drug of abuse, is widely used as a recreational drug at nightclubs and raves for its euphoric effects, and as a means of drug-facilitated sexual assault for its hypnotic/amnesic effects. GHB is known to bind to both GHB and GABA B receptors with its pharmacological effects mediated through GABA B receptors. Its overdose can lead to serious adverse effects such as respiratory depression, hypothermia, coma and death. In a recreational setting, GHB is typically not ingested alone and is commonly co-ingested with other club drugs such as ketamine and 3, 4-methylenedioxy methamphetamine (MDMA). Despite the widespread abuse of GHB and high risk of adverse effects, both alone and with co-ingestion of other club drugs, there currently exists no pharmacologic treatment for GHB overdose and current treatment for GHB overdose includes hospitalization, supportive care, and mechanical ventilation in cases of significant respiratory depression. The effect of the club drugs, ketamine and MDMA co-ingestion on GHB toxicokinetics/toxicodynamics (TK/TD) also remains unknown. The overall objective of my thesis is to identify TK/TD interactions between GHB and ketamine or MDMA and evaluate novel treatment strategies for overdose of these combinations. GHB exhibits nonlinear TK, characterized by saturable metabolism, saturable absorption, and saturable renal reabsorption mediated by monocarboxylate transporters (MCTs). MCT 1-4 have been characterized as proton-dependent transporters responsible for the transport of short chain monocarboxylates including L-lactate and GHB. The brain uptake of GHB is also mediated by MCT1. GHB is also a substrate for sodium dependent MCTs (SMCTs) which are similar in substrate specificity to MCTs, although they have a more limited tissue distribution. Previous studies in our laboratory have shown that intravenous administration of MCT inhibitors, such as L-lactate and luteolin, increases the renal and total clearance of GHB in rats by blocking its MCT-mediated active renal reabsorption in the kidney. Thus, MCT inhibition represents a potential therapeutic strategy for the treatment of GHB overdose. An improvement in the pharmacological effects of GHB such as sedation, hypothermia and respiratory depression has also been demonstrated following treatment with GABA B receptor antagonists. However, the use of MCT inhibition and GABA B receptor antagonism as potential treatment strategies for GHB in combination with other club drugs needs to be further investigated. Our hypothesis is that co-ingestion of GHB with other club drugs results in enhanced toxicity due to TK/TD interactions, and that the use of MCT inhibitors represents a potential treatment strategy for GHB alone, as well as with club drug co-administration. The overall objectives of this thesis were 1) to characterize the effects of ketamine and MDMA on GHB TK/TD, and 2) to evaluate the use of MCT inhibition and specific receptor antagonism as potential treatment strategies for GHB overdose when co-administered with other club drugs. All of our studies were performed in male Sprague-Dawley rats and the TK/TD interactions were evaluated using TK assessments and end points of sedation, respiratory depression and lethality. We studied the effects of a novel, highly potent MCT1 inhibitor (AR-C155858 K i value ~2.3 nM) in addition to L-lactate on GHB TK/TD when given alone or in the presence of ketamine or MDMA. A semi-physiological TK/TD model was developed to describe the interaction between GHB and the novel MCT inhibitor, AR-C155858. Significant findings: The results of this research demonstrated that MCTs play a predominant role in GHB transport at higher concentrations as seen in overdose, with a limited role of SMCTs. The novel, highly potent MCT1 inhibitor, AR-C155858 represents a potential treatment option for GHB overdose, due to increased GHB elimination, decreased MCT-mediated brain uptake, and rapid improvement in GHB-induced respiratory depression. The TK/TD model captured the interaction between GHB and AR-C155858 reasonably well with the mechanism of inhibition being non-competitive in nature. Ketamine could lead to potentially adverse drug interactions when co-ingested with GHB, as demonstrated by the increase in sleep time, respiratory depression and lethality in our studies. On the other hand, we observed limited TK/TD interactions between GHB and MDMA. Additionally, MCT and GABA B receptor antagonism represent potential treatment strategies for GHB overdose when ingested alone or with other club drugs such as ketamine and MDMA. In summary, significant TK/TD interactions were observed between the drugs of abuse, GHB and ketamine, with limited interactions between GHB and MDMA. MCT inhibition and GABA B receptor antagonism can serve as potential treatment strategies for GHB overdose when GHB is co-ingested with ketamine or MDMA. The TK/TD model can be used as a predictive tool to assess the effects of other MCT inhibitors as potential treatment strategies for GHB overdose and to assess the timing of administration of the inhibitor relative to GHB ingestion.