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，孕妇使用大麻 妇女正在增加。大约4％的孕妇都使用大麻欲望研究，表明 怀孕期间的大麻暴露对发育中的胎儿会产生负面影响。这是重要的 公共卫生问题。但是，描述使用大麻对怀孕结果的影响已经遭受 由于缺乏对大麻活性成分的药代动力学的了解，∆9-- 四氢大麻酚（THC）在怀孕期间发生了变化，并且由于缺乏可靠的生物标志物来量化 大麻使用和暴露水平。实际上，目前对驱动个人间个体的过程的知识 THC处置的可变性在很大程度上未知。现有数据表明，THC主要由 CYP2C9的CYP3A4贡献很小。几项研究表明，消除了主要 THC，11-OH-THC和11-NOR-羧基THC的代谢产物由UGT1A酶介导。这很重要 在孕妇的THC处置性的背景下，CYP2C9和UGT1A酶已显示为 受雌二醇和糖皮质激素的调节，这是妊娠期间增加的主要雌性骑兵。 基于这些数据，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。我们建议这种增加可以是 从体外人类肝细胞和原发性肠粘膜培养实验中预测的机理预测 进行马匹治疗和创新的THC代谢实验。在这个项目的第一部分中，我们将 通过确定THC代谢和CYP2C9的变化的幅度来检验这些假设 治疗人肝细胞和冷冻保存肠后，UGT1A同工型表达 粘膜含有雌二醇和糖皮质激素。我们还将建立肝脂肪酸的结合 蛋白质（FABP）在体外影响THC及其代谢物的代谢和分布。 THC一直在 显示与脑Fabps结合，但是THC及其代谢物是否与肝脏和肠Fabps结合 未知。我们假设FABP结合指导THC代谢，并有助于大麻素 清除和向代谢酶递送。我们将在体外使用生化测试这种创新的假设 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。我们希望这些研究将构成整体的基础 人类怀孕期间THC处置的预测和建模。完成后，我们的学习将 提供有助于THC的个体变异性的过程的关键信息 药代动力学。这些研究还将提供第二个数据，以允许对THC代谢组进行建模 人类血浆和尿液作为消费量和消费后的时间的函数 影响人类THC暴露的可靠生物标志物的发展。