Gamma-hydroxybutyrate: Toxicokinetics, Toxicodynamics and Treatment Strategies

State University Of New York At Buffalo, Buffalo NY

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Abstract

y-Hydroxybutyrate (GHB) remains a popular drug of abuse, commonly known as liquid ecstasy; it is often[unreadable] ingested with alcohol, with other drugs of abuse, or as its precursors y-butyrolactone and 1, 4-butanediol. GHB[unreadable] intoxication results in CNS and respiratory depression and overdoses result in coma and death. A recent[unreadable] review stated that GHB was the second most common drug detected in urine of young people presenting with[unreadable] drug-induced coma, just behind cocaine. There is currently no specific treatment for GHB overdoses. The goal[unreadable] of this proposal is to identify specific therapeutic interventions for the treatment of GHB overdoses, when GHB[unreadable] is ingested alone or with ethanol. We have reported that GHB undergoes concentration-dependent[unreadable] reabsorption in the kidney, due to transport by monocarboxylate transporters (MCTs), and that the[unreadable] administration of MCT inhibitors can increase the renal and total clearances of GHB. Results from our[unreadable] Preliminary Studies indicate that low doses of L-lactate combined with mannitol (an osmotic diuretic) increase[unreadable] GHB renal and total clearances, decrease serum concentrations, and decrease the return to righting reflex[unreadable] (RRR), a pharmacological end-point in rats, following high doses of GHB: the combined treatment resulted in[unreadable] an additive/synergistic effect on RRR. Our hypothesis is that administration of MCT inhibitors alone, or[unreadable] combined with mannitol, represents potential strategies for treating patients following overdoses of GHB. Our[unreadable] specific aims are: (1) To determine the mechanism(s) underlying the effect of MCT inhibitors on GHB[unreadable] toxicokinetics (TK) and toxicodynamics (TD). We will test the hypothesis that MCT inhibitors alter the TK and[unreadable] TD of GHB by multiple mechanisms: increased renal clearance of GHB resulting in an increased total[unreadable] clearance; inhibition of GHB brain uptake; and decreased formation of GABA in the brain. 2) To determine the[unreadable] effects of mannitol on GHB TK and TD, and the mechanism(s) underlying the enhanced pharmacological effect[unreadable] of L-lactate produced by concomitant mannitol administration. (3) To determine the mechanisms for the effect[unreadable] of ethanol on the TK/TD of GHB, and the efficacy of MCT inhibitors and mannitol on GHB TK and TD following[unreadable] the concomitant administration of ethanol. (4) To perform a clinical study in normal volunteers to evaluate the[unreadable] efficacy of L-lactate/mannitol treatment in increasing the elimination and decreasing plasma concentrations of[unreadable] GHB. Methods used in the proposal include in vivo studies in rats to determine plasma, brain tissue and[unreadable] extracellular fluid (ECF) concentrations (by microdialysis) of GHB and the neurotransmitter y-aminobutyric acid[unreadable] (GABA). The concentration-effect (RRR) relationship for GHB will be determined. Effects on brain uptake will[unreadable] be determined using in situ brain perfusion, and in vitro studies of GHB brain metabolism will utilize[unreadable] mitochondrial and cytosolic tissue preparations. The clinical study will provide "proof-of-concept" that the[unreadable] administration of L-lactate and mannitol can increase the elimination of GHB in humans, thereby representing[unreadable] a potential treatment for GHB overdoses.