PBPK prediction and verification of maternal-fetal exposure to cannabinoids

母胎大麻素暴露的 PBPK 预测和验证

• 批准号: 10231037
• 负责人: JASHVANT D Unadkat
• 金额: $ 52.34万
• 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/10231037
• 关键词: 17 year old; 18 year old; Address; Adolescence; Affect; American; Animals; Attentional deficit; Behavioral; Blood; Brain; CNR1 gene; Cannabinoids; Cannabis; Cessation of life; Chronic; Clinical Research; Consensus; Consumption; Data; Development; Discipline of obstetrics; Dose; Exposure to; Fetal Resorption; Fetal Tissues; Fetus; Gynecology; Health; Human; Impairment; In Vitro; Infection; Inhalation; Inhalation Drug Administration; Link; Low Birth Weight Infant; Male Adolescents; Marijuana; Maternal Exposure; Mental disorders; Meta-Analysis; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Neurologic; Odds Ratio; Oral; Outcome; Pharmaceutical Preparations; Pharmacology; Placenta; Plasma; Pregnancy; Pregnant Women; Prevalence; Problem Solving; Proteomics; Public Health; Race; Recommendation; Reporting; Resources; Risk; Rodent; Sampling; Schizophrenia; Signal Transduction; Smoking; System; THC exposure; Tetrahydrocannabinol; Third Pregnancy Trimester; Tissues; Tobacco; Toxic effect; United States National Academy of Sciences; Venous; Weight Gain; Woman; adverse outcome; animal data; axon growth; brain tissue; cognitive process; college; developmental neurotoxicity; drug of abuse; elective abortion; executive function; fetal; fetal marijuana exposure; illicit drug use; in utero; in vivo; innovation; marijuana use; marijuana use in pregnancy; maternal marijuana use; metabolomics; model development; models and simulation; neonatal death; neonatal morbidity; neonatal outcome; novel; perinatal outcomes; perpetrators; physiologically based pharmacokinetics; pregnant; prenatal; prenatal exposure; tool; transcriptomics

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. THC can dysregulate cannabinoid receptor 1 signaling during pregnancy and can result in adverse outcomes such as impaired fetal brain development, lower birth weight, increased fetal resorption, and even in utero deaths. THC can impact axon growth in the developing mouse fetal brain. Chronic exposure to THC leads to long-term behavioral deficits in male adolescent mice, akin to those observed in schizophrenia. However, these rodent 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. For many reasons, observational clinical studies in pregnant women who use marijuana are not informative as to whether marijuana is safe when used during pregnancy. Due to the limitations of all the above approaches, we propose here a systems pharmacology approach to begin to address this significant public health question. Through data obtained by this project and Projects 1 & 2, we will predict and then verify the magnitude of maternal-placental-fetal exposure to THC and its psychoactive metabolite, 11-OH-THC, throughout pregnancy, after both oral and inhalational (smoking) use of marijuana. To do so, we will refine and extend a novel maternal-fetal Physiologically Based PharmacoKinetic (m-f-PBPK) model we have developed. 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. Our approach uses novel and innovative tools (e.g. m-f-PBPK model, development of an inhalational m-f-PBPK model, quantitative targeted proteomics, transcriptomics, proteomics and metabolomics) to address a compelling public health question. 1

在美国，在孕妇中使用大麻（大麻）的患病率高达14％ 在12-18岁的孕妇中。美国妇产科建议 孕妇避免了大麻，因为证据表明它会影响胎儿，并可能干扰大脑 发展。动物的研究似乎支持这一建议。虽然其他构成 大麻不能打折，一般科学共识是Δ9-四氢大麻酚（THC）， 大麻中最丰富和精神活性的成分是发展的可能性 大麻的神经毒性。 THC可以在怀孕期间失调的大麻素受体1信号传导和 可能导致预后的结果，例如胎儿脑发育受损，降低出生体重，增加 胎儿解决，甚至在子宫死亡中。 THC会影响发育中的小鼠胎儿大脑的轴突生长。 长期暴露于THC导致长期行为定义在男性青少年小鼠中，类似于那些小鼠 在精神分裂症中观察到。但是，这些啮齿动物和体外研究是以高分毒剂量进行的 或浓度，因此对人类的适用性，在THC血浆浓度为亚 微摩尔是未知的。由于许多原因，使用的孕妇观察性临床研究 关于大麻在怀孕期间使用时是否安全，大麻毫无用处。由于 上述所有方法的局限性，我们在这里提出了一种系统药理学方法开始 解决这个重大的公共卫生问题。通过该项目和项目1和2获得的数据，我们 将预测然后验证孕产妇及其THC及其精神活性的大小 在口腔和意外（吸烟）使用大麻之后，整个怀孕期间的代谢产物，11-OH-THC。 为此，我们将完善并延长一种新型的基于生理生理的药代动力学（M-F-PBPK） 我们已经开发了模型。另外，我们将以探索方式确定 大麻素产生的任何分子特征表明在短期或长期发育神经毒性中产生任何分子特征。 人类。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，定量靶向蛋白质组学，转录组学，蛋白质组学和 代谢组学）解决一个令人信服的公共卫生问题。 1