Gamma-hydroxybutyrate: Toxicokinetics, Toxicodynamics and Treatment Strategies

γ-羟基丁酸酯（GHB）仍然是一种流行的滥用药物，通常被称为液体摇头丸;它经常被 与酒精、与其它滥用药物或作为其前体γ-丁内酯和1，4-丁二醇一起摄入。GHB 中毒导致CNS和呼吸抑制，过量导致昏迷和死亡。最近的一 审查指出，伽马-羟丁酸是第二个最常见的药物检测尿液中的年轻人提出的 药物引起的昏迷仅次于可卡因目前对GHB过量没有具体的治疗方法。目标 这项建议的一个重要目的是确定治疗伽马--羟丁酸过量的具体治疗干预措施， 单独摄入或与乙醇一起摄入。我们已经报道，GHB经历浓度依赖性 由于单羧酸转运蛋白（MCT）的转运， 给予MCT抑制剂可增加GHB的肾和总清除率。源自我们的 初步研究表明，低剂量的L-乳酸盐与甘露醇（渗透性利尿剂）联合使用， GHB肾脏和总清除率，降低血清浓度，并降低翻正反射恢复 (RRR)在大鼠中，高剂量GHB后的药理学终点：联合治疗导致 对RRR的累加/协同效应。我们的假设是，单独使用MCT抑制剂，或 与甘露醇组合，代表了治疗GHB过量患者的潜在策略。我们 具体目的是：（1）确定MCT抑制剂对GHB作用的机制 毒代动力学（TK）和毒代动力学（TD）。我们将检验MCT抑制剂改变TK的假设， 多种机制引起的GHB TD：GHB的肾脏清除率增加，导致总 清除;抑制GHB脑摄取;和减少脑中GABA的形成。2)确定 甘露醇对GHB TK和TD的影响，以及增强药理作用的机制 伴随甘露醇给药产生的L-乳酸盐。(3)为了确定这种影响的机制， 乙醇对GHB TK/TD的影响，以及MCT抑制剂和甘露醇对GHB TK和TD的疗效， 同时给予乙醇。(4)在正常志愿者中进行临床研究，以评估 L-乳酸/甘露醇治疗在增加消除和降低血药浓度方面的疗效 GHB.该提案中使用的方法包括在大鼠中进行体内研究，以确定血浆、脑组织和 GHB和神经递质γ-氨基丁酸的细胞外液（ECF）浓度（通过微透析） （GABA）。将确定GHB的浓度-效应（RRR）关系。对大脑摄取的影响将 使用原位脑灌注确定，GHB脑代谢的体外研究将利用 线粒体和胞质组织制备物。临床研究将提供“概念验证”， L-乳酸盐和甘露醇的施用可以增加人体中GHB的消除，从而代表 一种治疗伽马-羟丁酸过量的药物

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