Gamma-hydroxybutyrate: Toxicokinetics, Toxicodynamics and Treatment Strategies

羟基丁酸酯(GHB)仍然是一种常见的滥用药物，俗称液体摇头丸；它经常 与酒精或其他滥用药物一起摄入，或作为其前体--γ-丁内酯和1，4-丁二醇。GHB 中毒会导致中枢神经系统和呼吸抑制，过量会导致昏迷和死亡。最近 审查表明，GHB是在青少年尿液中检测到的第二种最常见的药物 药物引起的昏迷，仅次于可卡因。目前还没有针对GHB过量的具体治疗方法。目标是 这项建议的目的是确定治疗GHB过量的具体治疗干预措施，当GHB 是单独摄入还是与乙醇一起摄入。我们已经报道了GHb经历浓度依赖关系 由于单羧酸转运体(MCT)的转运，肾脏中的重吸收 给予MCT抑制剂可以增加肾组织对GHb的清除量和总清除量。结果来自我们的 初步研究表明，低剂量的L乳酸盐与甘露醇(一种渗透性利尿剂)联合使用会增加 GHb肾脏和完全清除，降低血清浓度，减少翻正反射的恢复 (RRR)，大鼠服用高剂量GHB后的药理学终点：联合治疗导致 RRR的相加/协同效应。我们的假设是单独使用MCT抑制剂，或 与甘露醇相结合，代表了治疗过量GHB患者的潜在策略。我们的 具体目标是：(1)确定MCT抑制剂对GHB作用的潜在机制(S) 毒物动力学(TK)和毒物动力学(TD)。我们将检验MCT抑制剂改变TK和TK的假设 通过多种机制实现GHB的TD：增加肾脏对GHB的清除量，从而导致总量增加 清除；抑制大脑对GHB的摄取；以及减少大脑中GABA的形成。2)确定 甘露醇对GHB、TK、TD的影响及药理作用机制(S) L-乳酸与甘露醇同时给药。(三)确定作用机制 乙醇对GHb TK/Td的影响及MCT抑制剂和甘露醇对GHb TK和Td的影响 随之而来的乙醇注射。(4)在正常志愿者中进行临床研究，以评估 L-乳酸/甘露醇治疗对提高血药浓度的疗效观察 羟基丁酸。该提案中使用的方法包括在大鼠体内进行研究，以确定血浆、脑组织和 细胞外液(ECF)中GHb和神经递质γ-氨基丁酸的浓度(微透析法) (GABA)。将确定GHB的浓度效应关系(RRR)。对大脑摄取的影响将 通过原位脑血流灌注来确定，并将利用体外研究GHB脑代谢 线粒体和胞浆组织制备。这项临床研究将提供“概念证明” 服用L乳酸盐和甘露醇可增加人体对GHb的清除，从而代表 一种治疗GHB过量的潜在方法。

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.