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

摘要 伽马-羟丁酸酯(GHB)是一种流行的滥用药物，用于狂欢和药物促进性行为 由于它的快感、催情和镇静作用而造成的攻击。每年与羟基丁酸相关的死亡人数 自20世纪90年代以来，在美国、英国、西欧和 澳大利亚。在过去的十年里，由于流行，GHB在LBGTQ社区的使用量一直在增加 一种被称为化学性行为的现象。在用于化学性行为的药物中，GHB最有可能导致急性 服药过量。依赖质子和钠的单羧酸转运体(MCTs/SMCTs)参与 GHB跨生物重要屏障和组织的运输及其在肾脏中的表达 清除和脑分布。初步数据表明，GHB毒代动力学(血浆浓度 和肾脏清除)在女性性激素的存在和不存在的情况下会发生变化。此外，我们还拥有 证明了男性和女性的性激素调节肾脏中的单羧酸转运体，以及 在发情周期中，男性和女性之间的GHB肾脏清除量的差异与 肾脏单羧酸转运体表达的变化。尽管性激素有可能调节 GHB肾清除量和组织分布，文献中缺乏关于 性激素和跨性激素治疗对GHB毒代动力学和毒性的影响。这件事的重点是 应用于研究性和跨性别激素治疗反应的GHB毒代动力学和 性激素依赖性调节肾和血脑屏障表达的机制研究 单羧酸转运体。我们的总体假设是GHB毒代动力学的变异性和过量用药风险 这是性激素依赖的调节单羧酸转运体的结果，该转运体控制GHB的清除和 分发。我们提出了两个具体的目标来评估这一假说，利用体内的性行为和 跨性别激素替代、分子生物学和毒物动力学技术。第一个具体目标 研究GHB的毒代动力学和对性激素和跨性激素治疗的毒性反应。我们的 这一目标的假设是[1]GHB肾脏清除量和全身暴露(AUC)将因此而改变 对个体雄性和雌性性激素；[2]雄性和暴露于睾丸素的动物将有 由于肾脏清除量降低，急性过量用药的风险增加。在第二个目标中，我们将调查 性激素对肾脏和血脑屏障MCTs和SMCTs的调节。我们的假设是性和交配- 性激素治疗会以不同的方式调节单羧酸转运体的表达，这种调节是 性激素受体依赖。这项建议代表了我们以前工作的新扩展，并将 进一步加深了我们对性激素依赖的药物清除调节机制的理解，以及由此产生的 毒物动力学后果，并将有助于确定GHB过量使用风险较大的人群。

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.