GHB Toxicokinetics: Role of sex hormone dependent monocarboxylate transporter regulation and potential for altered overdose risk in transgender men and women

摘要 γ-羟基丁酸（GHB）是一种流行的滥用药物，用于狂欢和药物促进性行为。 由于它的欣快、催情和镇静作用而受到攻击。每年与GHB相关的死亡人数 自20世纪90年代以来，在美国、英国、西欧和 澳大利亚在过去十年中，伽马--羟丁酸的使用在LBGTQ社区一直在增加，原因是 一种叫做化学性行为的现象在用于化学性行为的药物中，GHB最有可能引起急性 服药过量质子和钠依赖性单羧酸转运蛋白（MCT/SMCT）参与了 GHB跨生物重要屏障和组织的转运，其表达控制GHB肾 清除率和大脑分布。初步数据表明，GHB毒代动力学（血浆浓度 和肾清除率）在存在和不存在雌性激素的情况下发生改变。您因前述 证明了男性和女性性激素调节肾脏中的单羧酸转运蛋白， GHB肾清除率在整个发情周期的差异，男性和女性之间是一致的， 肾脏单羧酸转运蛋白表达的变化。尽管性激素有可能调节 GHB肾清除率和组织分布，文献中关于GHB的信息很少。 性别和交叉性激素处理对GHB毒代动力学和毒性影响的重点 应用于研究GHB对性别和跨性别激素治疗的毒代动力学反应， 确定调节肾和血脑屏障（BBB）表达的性别依赖机制 单羧酸转运蛋白。我们的总体假设是GHB毒代动力学和过量风险的变化 由控制GHB清除的单羧酸转运蛋白的性激素依赖性调节引起， 分布我们提出了两个具体的目标，以评估这一假设利用体内模型的性别和 跨性别激素替代、分子生物学和毒代动力学技术。第一个具体目标 研究GHB毒代动力学和毒性对性别和跨性别激素治疗的反应。我们 这一目标的假设是[1] GHB的肾脏清除率和全身暴露量（AUC）将随着反应而改变， 男性和女性的性激素; [2]男性和动物暴露于睾丸激素将有一个 由于肾脏清除率降低，急性药物过量风险增加。在我们的第二个目标中，我们将研究 肾脏和BBB MCT和SMCT的性别依赖性调节。我们的假设是性别和交叉- 性激素处理将不同地调节单羧酸转运蛋白的表达，这种调节是 性激素受体依赖性这个建议代表了我们以前工作的一个新的扩展， 进一步我们对药物清除的性别依赖性调节机制的理解，以及由此产生的 这将有助于查明伽马--羟丁酸过量风险较大的人群。

ABSTRACT Gamma-hydroxybutyrate (GHB), is a popular drug of abuse utilized at raves and in drug-facilitate sexual assault due to its’ euphoric, aphrodisiac, and sedative effects. The annual number of GHB-associated deaths has continued to increase since the 1990s in the United States, the United Kingdom, Western Europe and Australia. In the last decade the use of GHB has been increasing in the LBGTQ community due to the prevalence of a phenomenon referred to as chemsex. Of the drugs used for chemsex, GHB is the most likely to cause acute overdose. Proton- and sodium-dependent monocarboxylate transporters (MCTs/SMCTs) are involved in the transport of GHB across biologically important barriers and tissues, and their expression governs GHB renal clearance and brain distribution. Preliminary data demonstrates that GHB toxicokinetics (plasma concentrations and renal clearance) are altered in the presence and absence of female sex hormones. Further, we have demonstrated that male and female sex hormones regulate monocarboxylate transporters in the kidney, and differences in GHB renal clearance over the estrous cycle, and between males and females are consistent with the changes in renal monocarboxylate transporter expression. Despite the potential for sex hormones to regulate GHB renal clearance and tissue distribution, there is a paucity of information in the literature regarding the influence of sex and cross-sex hormone treatment on GHB toxicokinetics and toxicity. The focus of this application is on investigating GHB toxicokinetics in response to sex and cross-sex hormone therapy and identifying the sex hormone-dependent mechanisms regulating expression of renal and blood brain barrier (BBB) monocarboxylate transporters. Our overall hypothesis is that variability in GHB toxicokinetics and overdose risk result from sex hormone-dependent regulation of monocarboxylate transporters that govern GHB clearance and distribution. We have proposed two specific aims to evaluate this hypothesis utilizing in vivo models of sex and cross-sex hormone replacement, molecular biological and toxicokinetic techniques. The first specific aim investigates GHB toxicokinetics and toxicity in response to sex and cross-sex hormone treatment. Our hypotheses for this aim are that [1] GHB renal clearance and systemic exposure (AUC) will be altered in response to individual male and female sex hormones; [2] males, and animals exposed to testosterone will have an increased risk of acute overdose due to decreased renal clearance. In our second aim, we will investigate the sex hormone-dependent regulation of renal and BBB MCTs and SMCTs. Our hypotheses are that sex and cross- sex hormone treatment will differently regulate monocarboxylate transporter expression, and this regulation is sex hormone receptor dependent. This proposal represents a novel extension of our previous work, and will further our mechanistic understanding of sex hormone-dependent regulation of drug clearance, and the resultant toxicokinetic consequences, and will help to identify populations with a greater risk of GHB overdose.