Mechanisms of Regulation of Cannabinoid Disposition

大麻素处置的调节机制

• 批准号: 10463602
• 负责人: Nina Isoherranen
• 金额: $ 41.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463602
• 关键词: Adverse effects; Affect; Age; Age-Years; Animal Model; Binding; Binding Proteins; Biochemical; Biological Markers; Brain; CYP2C9 gene; CYP3A4 gene; Cannabinoids; Cannabis; Cannabis Abuse; Cells; Clinical Research; Cohort Studies; Collaborations; Consumption; Cryopreservation; Data; Development; Drug Kinetics; Enzyme Induction; Enzymes; Estradiol; Estrogens; Evaluation; Exposure to; Family; Female; Fetal Development; Foundations; Glucocorticoids; Glucuronides; Goals; Gut Mucosa; Hepatic; Hepatocyte; Hormones; Human; Hydrocortisone; In Vitro; Individual; Intake; Intestinal Mucosa; Intestines; Knowledge; Liver; Mediating; Metabolic; Metabolism; Methods; Minor; Modeling; Movement; Outcome; Pharmacology; Plasma; Play; Pregnancy; Pregnancy Outcome; Pregnant Women; Process; Protein Isoforms; Public Health; Regulation; Research Personnel; Risk; Role; Seminal; Serum; System; THC exposure; Techniques; Testing; Tetrahydrocannabinol; Time; UGT1A1 gene; Urine; Validation; Woman; Work; base; cellular targeting; drug of abuse; experimental study; fatty acid-binding proteins; fetal; fetal marijuana exposure; in vivo; infant outcome; innovation; inter-individual variation; intestinal fatty acid binding protein; marijuana legalization; marijuana use; metabolome; novel; physiologically based pharmacokinetics; predictive modeling; prenatal exposure; reproductive; response; simulation

Cannabis is the most commonly used illicit substance in the world, and the use of cannabis by pregnant women is increasing. Approximately 4% of all pregnant women use cannabis despite studies suggesting that cannabis exposure during pregnancy has negative consequences to the developing fetus. This is a significant public health concern. However, delineating the impact of cannabis use on pregnancy outcomes has suffered from lack of understanding of how the pharmacokinetics of the active component of cannabis, ∆9- tetrahydrocannabinol (THC) is altered during pregnancy, and from lack of a reliable biomarker to quantify cannabis usage and exposure levels. In fact, at present the knowledge of processes that drive inter-individual variability in THC disposition are largely unknown. Existing data suggests that THC is mainly cleared by CYP2C9 with a minor contribution from CYP3A4. Several studies have shown that the elimination of the major metabolites of THC, 11-OH-THC and 11-nor-carboxy-THC is mediated by UGT1A enzymes. This is important in the context of THC disposition in pregnant women as CYP2C9 and UGT1A enzymes have been shown to be regulated by estradiol and glucocorticoids, major female hormones that are increased during pregnancy. Based on this data, we hypothesize that the clearance of THC and its metabolites is significantly increased with increasing estradiol and glucocorticoid concentrations. We propose that this increase can be mechanistically predicted from in vitro human hepatocyte and primary intestinal mucosal culture experiments with hormone treatments and innovative THC metabolism experiments. In the first part of this project we will test these hypotheses by determining the magnitude of changes in THC metabolism and in CYP2C9, CYP3A4 and UGT1A isoform expression following treatment of human hepatocytes and cryopreserved intestinal mucosa with estradiol and glucocorticoids. We will also establish how hepatic and intestinal fatty acid binding proteins (FABPs) affect the metabolism and distribution of THC and its metabolites in vitro. THC has been shown to bind to brain FABPs, but whether THC and its metabolites bind to liver and intestinal FABPs is unknown. We hypothesize that FABP binding directs THC metabolism, and contributes to cannabinoid clearance and delivery to metabolic enzymes. We will test this innovative hypothesis in vitro using biochemical methods. In the second part of this proposal, we will test in a clinical study whether estrogens and cortisol induce THC metabolism and exposure. We expect that these studies will form the foundation for overall prediction and modeling of THC disposition during human pregnancy. When completed, our studies will provide critical information of the processes that contribute to inter-individual variability of THC pharmacokinetics. These studies will also provide seminal data to allow modeling of THC metabolome in human plasma and urine as a function of THC consumption and time after consumption, making a significant impact on development of reliable biomarkers of THC exposures in humans.

大麻是世界上最常用的非法物质，孕妇使用大麻 女性人数正在增加。大约4%的孕妇使用大麻，尽管研究表明 怀孕期间接触大麻对发育中的胎儿有负面影响。这是一个意义重大的 公共卫生问题。然而，描述大麻使用对妊娠结局的影响却受到了影响 由于缺乏对大麻活性成分∆9的药代动力学的了解- 四氢大麻酚(THC)在怀孕期间会发生变化，缺乏可靠的生物标记物来定量 大麻的使用和暴露水平。事实上，目前关于推动个人之间的过程的知识 THC处置的可变性在很大程度上是未知的。现有数据表明，THC主要是通过 细胞色素P3A4对细胞色素P3C9的贡献较小。多项研究表明，消除主要的 THC、11-OH-THC和11-Nor-Carxy-THC的代谢产物是由UGT1A酶介导的。这事很重要 在孕妇的THC处置的背景下，如CYP2C9和UGT1A酶已被证明 受雌激素和糖皮质激素的调节，这是怀孕期间增加的主要女性荷尔蒙。 基于这一数据，我们假设THC及其代谢物的清除量显著增加 随着雌二醇和糖皮质激素浓度的增加。我们建议，这一增长可以是 从体外人肝细胞和原代肠道粘膜培养实验中预测的机制 通过激素治疗和创新的THC新陈代谢实验。在这个项目的第一部分，我们将 通过确定新陈代谢和细胞色素P4502C9、3A4的变化幅度来检验这些假说 和UGT1a亚型在人肝细胞和冷冻肠道处理后的表达 粘膜中含有雌二醇和糖皮质激素。我们还将确定肝脏和肠道脂肪酸如何结合 蛋白质(FABP)在体外影响THC及其代谢产物的代谢和分布。THC已经被 显示与脑FABP结合，但THC及其代谢产物是否与肝脏和肠道FABP结合 未知。我们假设FABP结合引导新陈代谢，并促进大麻素的合成 清除并传递给新陈代谢酶。我们将使用生物化学在体外测试这一创新假说。 方法：研究方法。在这项建议的第二部分，我们将在临床研究中测试雌激素和皮质醇 诱导新陈代谢和暴露。我们期望这些研究将构成整体 人类妊娠期THC倾向的预测和建模。完成后，我们的研究将 提供造成THC个体间差异的过程的关键信息 药物动力学。这些研究还将提供开创性的数据，以便对THC代谢组进行建模 人体血浆和尿液作为THC摄入量和摄取后时间的函数，使显著 对人类暴露于THC的可靠生物标志物发展的影响。