Mechanisms of Regulation of Cannabinoid Disposition

大麻素处置的调节机制

• 批准号: 10231038
• 负责人: Nina Isoherranen
• 金额: $ 41.6万
• 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/10231038
• 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，孕妇吸食大麻 女性正在增加。尽管研究表明，大约 4% 的孕妇使用大麻 怀孕期间接触大麻会对发育中的胎儿产生负面影响。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受到了影响 由于缺乏对大麻活性成分的药代动力学的了解，Δ9- 四氢大麻酚（THC）在怀孕期间发生变化，并且由于缺乏可靠的生物标志物来量化 大麻的使用和接触水平。事实上，目前驱动个体间的过程的知识 THC 分布的变异性在很大程度上是未知的。现有数据表明 THC 主要通过以下方式清除： CYP2C9 与 CYP3A4 的贡献较小。多项研究表明，消除主要 THC、11-OH-THC 和 11-正羧基-THC 的代谢物由 UGT1A 酶介导。这很重要 在孕妇 THC 处置的背景下，CYP2C9 和 UGT1A 酶已被证明可以 受到雌二醇和糖皮质激素的调节，这是怀孕期间增加的主要女性激素。 根据这些数据，我们假设 THC 及其代谢物的清除率显着增加 随着雌二醇和糖皮质激素浓度的增加。我们建议，这一增加可以 从体外人肝细胞和原代肠粘膜培养实验中进行机械预测 通过激素治疗和创新的 THC 代谢实验。在这个项目的第一部分，我们将 通过确定 THC 代谢和 CYP2C9、CYP3A4 的变化幅度来检验这些假设 人肝细胞和冷冻保存的肠道处理后 UGT1A 亚型的表达 粘膜用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）影响 THC 及其代谢物的体外代谢和分布。 THC 已 研究显示 THC 及其代谢物是否与大脑 FABP 结合，但是否与肝脏和肠道 FABP 结合尚不清楚。 未知。我们假设 FABP 结合指导 THC 代谢，并有助于大麻素 清除并输送至代谢酶。我们将使用生化方法在体外测试这一创新假设 方法。在该提案的第二部分中，我们将在临床研究中测试雌激素和皮质醇是否 诱导 THC 代谢和暴露。我们期望这些研究将成为整体的基础 人类怀孕期间 THC 分布的预测和建模。完成后，我们的研究将 提供导致 THC 个体间差异的过程的关键信息 药代动力学。这些研究还将提供开创性数据，以便对 THC 代谢组进行建模 人类血浆和尿液作为 THC 消耗量和消耗后时间的函数，使得 对人类 THC 暴露可靠生物标志物开发的影响。