Pharmacology of Drugs of Abuse During Pregnancy

怀孕期间滥用药物的药理学

• 批准号: 10688212
• 负责人: JASHVANT D Unadkat
• 金额: $ 153.99万
• 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/10688212
• 关键词: 18 year old; Address; Adolescence; Affect; American; Animals; Brain; CNR1 gene; Cannabinoids; Cannabis; Cells; Child; Clinical Trials; Consensus; Consumption; Controlled Clinical Trials; Data; Development; Discipline of obstetrics; Dose; Drug Kinetics; Drug Transport; Ethics; Exposure to; Fetal Liver; Fetus; Frequencies; Funding; Future; Gestational Age; Glucuronides; Goals; Gynecology; Human; Impairment; In Vitro; Infant; Infection; Inhalation; Knowledge; Link; Marijuana; Maternal Exposure; Mental disorders; Meta-Analysis; Metabolic; Metabolism; Methods; Molecular Profiling; Morbidity - disease rate; Mus; Neurologic; Neurons; Odds Ratio; Organ; Outcome; Perfusion; Pharmaceutical Preparations; Pharmacology; Placenta; Plasma; Pregnancy; Pregnant Women; Prevalence; Proteomics; Public Health; Race; Recommendation; Risk; Rodent; Schizophrenia; Schools; Signal Transduction; System; THC concentration; Testing; Tetrahydrocannabinol; Tissues; Tobacco; Toxic effect; United States National Institutes of Health; Visual attention; adverse outcome; age related; animal data; axon growth; clinically relevant; college; data integration; design; developmental neurotoxicity; drug disposition; drug of abuse; fetal; fetal marijuana exposure; human data; illicit drug use; in vivo; innovation; marijuana use; marijuana use in pregnancy; maternal marijuana use; metabolome; metabolomics; models and simulation; neonatal death; neonatal morbidity; neonatal outcome; novel; perpetrators; pharmacokinetic model; physiologically based pharmacokinetics; placental transfer; pregnant; prenatal; prenatal exposure; programs; risk prediction; statistics; tool; unethical; visual memory

Use of marijuana (cannabis) among pregnant women in the US is increasing with prevalence as high as 14% among 12–18 year old pregnant women. The American College of Obstetrics and Gynecology recommends that pregnant women avoid marijuana due to evidence that it affects the fetus and may interfere with brain development. Studies in animals appear to support this recommendation. Although other constituents of marijuana cannot be discounted, the general scientific consensus is that ∆9-tetrahydrocannabinol (THC), the most abundant and psychoactive component in marijuana, is the likely perpetrator of the developmental neurotoxicity of marijuana. However, these animal and in vitro studies were conducted at high THC doses or concentrations and therefore their applicability to humans, where THC plasma concentrations are sub-micromolar, is unknown. On the other hand, human data on fetal and infant developmental outcomes due to marijuana use during pregnancy are limited, confounded by other factors and remain controversial. Conducting a controlled clinical trial to determine if marijuana results in negative fetal/neonatal outcomes is unethical. Therefore, alternative approaches to determine fetal outcomes of marijuana use during pregnancy need to be explored. However, this can only be achieved when the fetal exposure to THC and its active metabolite,11-OH-THC, has been addressed and accurately predicted. To achieve this goal, we propose a systems pharmacology approach to begin to address this significant public health problem and test the central hypothesis: Maternal-fetal exposure for THC/11-OH-THC during pregnancy can be predicted through innovative in vitro and in vivo studies integrated through maternal-fetal PBPK modeling and simulation (m-f-PBPK M & S). Fetal exposure to THC/11-OH-THC will be dependent on their maternal disposition, placental transport/metabolism and fetal clearance. Fetal exposure to THC/11-OH-THC will drive their fetal toxicity. Therefore, the projects of this P01 are designed to: 1) understand fetal exposure to THC/11-OH-THC by characterizing metabolism and transport of THC/11-OH-THC in maternal organs, placenta and fetus (Project 1); 2) predict the changes in maternal exposure to THC and its comprehensive metabolome including 11-OH-THC, 11-nor-COOH-THC and the glucuronides, throughout pregnancy, and the mechanistic basis for these changes (Project 2); and 3) predict and verify gestational age- dependent placental-fetal exposure to THC/11-OH-THC through PBPK M & S by integrating the data from the above two projects (Project 3). In addition, in an exploratory manner, we will determine whether these cannabinoids produce any molecular signatures indicative of short or long-term developmental neurotoxicity in humans (Project 3). Our approach uses novel and innovative tools (e.g. m-f-PBPK model, development of an inhalational m-f-PBPK model, perfused human placenta, quantitative targeted proteomics and metabolomics) to address a compelling public health question.

美国孕妇吸食大麻的趋势不断增加，患病率高达 12-18 岁孕妇中这一比例为 14%。 妇科建议孕妇避免吸食大麻，因为有证据表明它会影响 动物研究似乎支持这一点。 尽管大麻的其他成分不容忽视，但一般科学性。 共识是，Δ9-四氢大麻酚（THC）是大麻中最丰富且具有精神活性的成分 大麻可能是大麻发育神经毒性的罪魁祸首。 体外研究是在高 THC 剂量或浓度下进行的，因此它们的适用性 人类的 THC 血浆浓度为亚微摩尔，但人类数据尚不清楚。 怀孕期间吸食大麻对胎儿和婴儿发育结果的影响有限， 进行一项对照临床试验以确定大麻是否会导致这一结果仍存在争议。 因此，确定胎儿结局的替代方法是不道德的。 怀孕期间使用大麻的情况需要探索，但这只能在胎儿时期才能实现。 THC 及其活性代谢物 11-OH-THC 的暴露已得到解决并准确预测。 为了实现这一目标，我们提出了一种系统药理学方法来开始解决这一重要的公众问题 健康问题并检验中心假设：母婴期间 THC/11-OH-THC 暴露 可以通过创新的体外和体内研究来预测怀孕 母体-胎儿 PBPK 建模和模拟（m-f-PBPK M & S）。 取决于其母体处置、胎盘运输/代谢和胎儿清除率。 THC/11-OH-THC 会导致其胎儿毒性，因此，本 P01 的项目旨在： 1) 通过表征 THC/11-OH-THC 的代谢和转运，胎儿暴露于 THC/11-OH-THC 母体器官、胎盘和胎儿（项目 2）预测母体 THC 暴露及其变化 全面的代谢组，包括 11-OH-THC、11-去甲-COOH-THC 和葡萄糖醛酸苷 怀孕，以及这些变化的机制基础（项目 2）；以及 3）预测和验证孕龄- 通过 PBPK M & S 通过整合来自 另外，我们会以探索性的方式确定这些是否是上述两个项目。 大麻素产生任何表明短期或长期发育神经毒性的分子特征 人类（项目 3）。我们的方法使用新颖和创新的工具（例如 m-f-PBPK 模型、开发 吸入m-f-PBPK模型、灌注人胎盘、定量靶向蛋白质组学和代谢组学） 解决一个引人注目的公共卫生问题。

项目成果

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses.

开发一种新型母胎生理学药代动力学模型 I：通过模拟和敏感性分析深入了解决定胎儿药物暴露的因素。

• 发表时间: 2017-08
• 作者: Zhang, Zufei;Imperial, Marjorie Z;Patilea;Wedagedera, Janak;Gaohua, Lu;Unadkat, Jashvant D
• 通讯作者: Unadkat, Jashvant D

Estimation of Fetal-to-Maternal Unbound Steady-State Plasma Concentration Ratio of P-Glycoprotein and/or Breast Cancer Resistance Protein Substrate Drugs Using a Maternal-Fetal Physiologically Based Pharmacokinetic Model.

使用基于母体-胎儿生理学的药代动力学模型估计 P-糖蛋白和/或乳腺癌抗性蛋白底物药物的胎儿与母体未结合稳态血浆浓度比。

• 发表时间: 2022-05
• 作者: Peng, Jinfu;Ladumor, Mayur K;Unadkat, Jashvant D
• 通讯作者: Unadkat, Jashvant D

Characterizing and Quantifying Extrahepatic Metabolism of (-)-Δ9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, (±)-11-Hydroxy-Δ9-THC (11-OH-THC).

表征和量化 (-)-α9-四氢大麻酚 (THC) 及其精神活性代谢物 (±)-11-羟基-α9-THC (11-OH-THC) 的肝外代谢。

• 发表时间: 2022-06
• 作者: Kumar, Aditya R;Patilea;Anoshchenko, Olena;Unadkat, Jashvant D
• 通讯作者: Unadkat, Jashvant D

Predicting Regional Respiratory Tissue and Systemic Concentrations of Orally Inhaled Drugs through a Novel PBPK Model.

通过新型 PBPK 模型预测口服吸入药物的区域呼吸组织和全身浓度。

• 发表时间: 2022-05
• 作者: Ladumor, Mayur K;Unadkat, Jashvant D
• 通讯作者: Unadkat, Jashvant D

Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆9 -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.

了解灌注人胎盘中 (-)-α9-四氢大麻酚 (THC) 经胎盘转移的机制和程度，以预测体内胎儿 THC 暴露。

• 发表时间: 2023-08
• 影响因子: 6.7
• 作者: Kumar, Aditya R;Sheikh, Emily D;Monson, Joshua W;Ligon, Sarah E;Talley, Rebecca L;Dornisch, Elisabeth M;Howitz, Kamy J;Damicis, Jennifer R;Ieronimakis, Nicholas;Unadkat, Jashvant D
• 通讯作者: Unadkat, Jashvant D