GAMMA-HYDROXYBUTYRATE: TOXICOKINETICS, TOXICODYNAMICS AND TREATMENT STRATEGIES
MORRIS, MARILYN EMILY Principal Investigator
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y-Hydroxybutyrate (GHB) remains a popular drug of abuse, commonly known as liquid ecstasy; it is ofteningested with alcohol, with other drugs of abuse, or as its precursors y-butyrolactone and 1, 4-butanediol. GHBintoxication results in CNS and respiratory depression and overdoses result in coma and death. A recentreview stated that GHB was the second most common drug detected in urine of young people presenting withdrug-induced coma, just behind cocaine. There is currently no specific treatment for GHB overdoses. The goalof this proposal is to identify specific therapeutic interventions for the treatment of GHB overdoses, when GHBis ingested alone or with ethanol. We have reported that GHB undergoes concentration-dependentreabsorption in the kidney, due to transport by monocarboxylate transporters (MCTs), and that theadministration of MCT inhibitors can increase the renal and total clearances of GHB. Results from ourPreliminary Studies indicate that low doses of L-lactate combined with mannitol (an osmotic diuretic) increaseGHB renal and total clearances, decrease serum concentrations, and decrease the return to righting reflex(RRR), a pharmacological end-point in rats, following high doses of GHB: the combined treatment resulted inan additive/synergistic effect on RRR. Our hypothesis is that administration of MCT inhibitors alone, orcombined with mannitol, represents potential strategies for treating patients following overdoses of GHB. Ourspecific aims are: (1) To determine the mechanism(s) underlying the effect of MCT inhibitors on GHBtoxicokinetics (TK) and toxicodynamics (TD). We will test the hypothesis that MCT inhibitors alter the TK andTD of GHB by multiple mechanisms: increased renal clearance of GHB resulting in an increased totalclearance; inhibition of GHB brain uptake; and decreased formation of GABA in the brain. 2) To determine theeffects of mannitol on GHB TK and TD, and the mechanism(s) underlying the enhanced pharmacological effectof L-lactate produced by concomitant mannitol administration. (3) To determine the mechanisms for the effectof ethanol on the TK/TD of GHB, and the efficacy of MCT inhibitors and mannitol on GHB TK and TD followingthe concomitant administration of ethanol. (4) To perform a clinical study in normal volunteers to evaluate theefficacy of L-lactate/mannitol treatment in increasing the elimination and decreasing plasma concentrations ofGHB. Methods used in the proposal include in vivo studies in rats to determine plasma, brain tissue andextracellular fluid (ECF) concentrations (by microdialysis) of GHB and the neurotransmitter y-aminobutyric acid(GABA). The concentration-effect (RRR) relationship for GHB will be determined. Effects on brain uptake willbe determined using in situ brain perfusion, and in vitro studies of GHB brain metabolism will utilizemitochondrial and cytosolic tissue preparations. The clinical study will provide 'proof-of-concept' that theadministration of L-lactate and mannitol can increase the elimination of GHB in humans, thereby representinga potential treatment for GHB overdoses.