Pharmacology of Drugs of Abuse During Pregnancy

美国孕妇对大麻(大麻)的使用正在增加，流行率高达 在12-18岁孕妇中占14%。美国产科医学院 妇科建议孕妇避免吸食大麻，因为有证据表明它会影响 可能会影响胎儿的大脑发育。对动物的研究似乎支持这一观点。 推荐。尽管大麻的其他成分不能打折扣，但一般的科学研究 人们普遍认为，∆9-四氢大麻酚(THC)是大麻中含量最丰富、最具精神活性的成分 大麻可能是大麻发育神经毒性的肇事者。然而，这些动物 体外研究是在高剂量或高浓度下进行的，因此它们对 人类的血浆浓度在亚微摩尔以下，这是未知的。另一方面，人类数据 怀孕期间使用大麻对胎儿和婴儿发育结果的影响是有限的， 其他因素，并仍有争议。进行一项对照临床试验以确定大麻是否会导致 胎儿/新生儿的不良结局是不道德的。因此，确定胎儿结局的替代方法 需要对怀孕期间使用大麻的风险进行调查。然而，这只能在胎儿 暴露于THC及其活性代谢物11-OH-THC，已被解决并准确预测。至 为了实现这一目标，我们提出了一种系统药理学的方法来开始解决这一重要的公众 健康问题和检验中心假设：母婴接触THC/11-OH-THC 可以通过创新的体外和体内研究预测怀孕，通过 母婴PBPK建模与仿真(m-f-PBPK，M&S)。胎儿暴露于THC/11-OH-THC将 取决于母亲的性情、胎盘的运输/代谢和胎儿的排泄。胎儿暴露 THC/11-OH-THC会导致其胎儿毒性。因此，本次P01的项目旨在：1) 通过表征THC/11-OH-THC的代谢和转运了解胎儿对THC/11-OH-THC的暴露 在产妇器官、胎盘和胎儿中(项目1)；2)预测产妇接触THC和THC的变化。 全面的代谢体，包括11-OH-THC，11-Nor-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和S对胎盘-胎儿暴露于THC/11-OH-THC的依赖 以上两个项目(项目3)。此外，我们将以探索性的方式确定这些 大麻类化合物产生的任何分子特征都表明对小鼠的发育神经毒性短期或长期 人类(项目3)。我们的方法使用了新颖和创新的工具(例如m-f-PBPK模型、开发 吸入m-f-PBPK模型、灌流人胎盘、定量靶向蛋白质组学和代谢组学) 来解决一个引人注目的公共卫生问题。

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.