Pharmacology of Drugs of Abuse During Pregnancy

在美国，孕妇使用大麻（大麻）的比例越来越高， 12-18岁孕妇中为14%。美国产科学院 妇科建议孕妇避免大麻，因为有证据表明，它会影响 胎儿，可能会干扰大脑发育。对动物的研究似乎支持这一点 推荐虽然大麻的其他成分不能被忽视，但一般的科学研究表明， 共识是，大麻中最丰富的精神活性成分- 大麻，是大麻发育神经毒性的可能肇事者。然而，这些动物 体外研究是在高THC剂量或浓度下进行的，因此它们适用于 人类，其中THC血浆浓度是亚微摩尔，是未知的。另一方面，人类数据 由于怀孕期间使用大麻对胎儿和婴儿发育结果的影响有限， 其他因素，仍有争议。进行对照临床试验，以确定大麻是否会导致 胎儿/新生儿的阴性结果是不道德的。因此，确定胎儿结局的替代方法 在怀孕期间使用大麻需要探索。然而，这只能在胎儿 暴露于THC及其活性代谢物11-OH-THC的风险已经得到解决和准确预测。到 实现这一目标，我们提出了一个系统药理学的方法，开始，以解决这一重大公众 健康问题和测试中心假设：母亲-胎儿接触THC/11-OH-THC期间 怀孕可以通过创新的体外和体内研究预测， 母胎PBPK建模和模拟（m-f-PBPK M & S）。胎儿暴露于THC/11-OH-THC将 取决于母体倾向、胎盘转运/代谢和胎儿清除率。胎儿暴露 THC/11-OH-THC会导致胎儿毒性。因此，本P01项目设计为：1） 通过表征THC/11-OH-THC的代谢和转运，了解胎儿暴露于THC/11-OH-THC （2）预测母亲暴露于THC的变化及其对THC的影响（项目1） 全面的代谢物组，包括11-OH-THC，11-nor-COOH-THC和葡萄糖醛酸，贯穿始终 妊娠，以及这些变化的机制基础（项目2）;和3）预测和验证胎龄- 通过PBPK M & S，通过整合来自 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 大麻素产生任何指示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， 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） 来解决一个紧迫的公共卫生问题。

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.