Toxicodynamic and Toxicokinetic Based Treatment of γ-Hydroxybutyric Acid (GHB) Overdose
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γ-Hydroxybutyric acid (GHB) is a short chain fatty acid which was first discovered through its synthesis in 1874, and later found to be an endogenous compound in the human central nervous system. GHB is a structural analogue of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. GHB has several clinical indications as a sedative, treatment for narcolepsy and for alcohol withdrawal. Recently, GHB has been approved for Narcolepsy type I in pediatrics. The clinical utility of GHB is limited by its high abuse potential. GHB, and its prodrug γ-butyrolactone (GBL), are abused for many reasons including euphoric effects, anabolic effects via stimulation of the release of growth hormone, and to facilitate sexual assault. The abuse of GHB can lead to adverse side effects such as hypothermia, respiratory depression, coma and death. Currently there is no specific treatment for GHB overdose and intervention is limited to supportive care. GHB exerts its toxicodynamic (TD) effects as a partial GABAB receptor agonist. Previous studies in rats have indicated that administration of the potent GABAB antagonist SCH50911 five minutes prior to or after GHB administration reduces the TD effects of GHB. Administration of another GABAB antagonist, SGS742, also reduced sedation associated with GHB in rats. SGS742 is currently in clinical trials for Succinic Semialdehyde Dehydrogenase Deficiency (SSADH), a rare genetic condition which leads to elevated concentrations of GHB and GABA. GHB exhibits nonlinear kinetics through saturable absorption, saturable renal reabsorption and saturable metabolism. GHB is ionized at physiologic pH, and is dependent on transporters for many of its kinetic processes. This includes its absorption, renal reabsorption and uptake into its site of action in the brain at the GABAB receptor. One major transporter involved at these sites in Monocarboxylate transporter 1 (MCT1), a member of the solute carrier family (SLC16A1). Previous studies have shown that inhibition of MCT1 can reduce brain exposure of GHB, as well as plasma exposure through an increase in renal clearance (CLR). AR-C155858, a potent MCT1 inhibitor, has been utilized previously with GHB overdose and shown to reduce GHB TD/TK when administered 5 minutes after intravenous GHB. The compound was also effective at reducing GHB TK when administered 60 minutes after an oral dose of GHB in rats. Another MCT1 inhibitor with similar potency to AR-C155858, AZD3965, had not been investigated as a treatment for GHB overdose previously, but is in clinical trials for the treatment of solid tumor cancer as an MCT1 inhibitor. The hypothesis is MCT1 inhibition and GABAB antagonism are potential treatment options for GHB overdose through reduction of GHB exposure and reversal of GHB toxicity at its site of action at the GABAB receptor, respectively.