PBPK prediction and verification of maternal-fetal exposure to cannabinoids

母胎大麻素暴露的 PBPK 预测和验证

基本信息

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
项目类别：
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

项目摘要

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

美国孕妇吸食大麻的比例不断上升，比例高达 14% 美国妇产科学院建议 12-18 岁孕妇。孕妇避免吸食大麻，因为有证据表明大麻会影响胎儿并可能干扰大脑动物研究似乎支持这一建议，尽管其他成分。大麻不容小觑，一般科学共识是 Δ9-四氢大麻酚 (THC)，即大麻中最丰富且具有精神活性的成分，可能是发育障碍的肇事者 THC 的神经毒性会导致怀孕期间和怀孕期间的大麻素受体 1 信号失调。可能会导致不良后果，例如胎儿大脑发育受损、出生体重降低、体重增加胎儿吸收，甚至子宫内死亡，THC 都会影响发育中的小鼠胎儿大脑的轴突生长。长期接触 THC 会导致雄性青春期小鼠的长期行为缺陷，类似于那些然而，这些啮齿动物和体外研究是在高 THC 剂量下进行的。或浓度，因此它们对人类的适用性，其中 THC 血浆浓度低于微摩尔，由于多种原因，在孕妇中使用的观察性临床研究尚不清楚。由于怀孕期间使用大麻是否安全，因此无法提供信息。由于上述所有方法的局限性，我们在此提出一种系统药理学方法来开始通过该项目以及项目 1 和 2 获得的数据，我们解决了这一重大公共卫生问题。将预测并验证母体-胎盘-胎儿接触 THC 及其精神活性的程度代谢物 11-OH-THC，在整个怀孕期间、口服和吸入（吸烟）使用大麻后。为此，我们将完善和扩展一种新型母胎生理药代动力学 (m-f-PBPK) 此外，我们将以探索性的方式确定这些是否有效。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）来解决一个引人注目的公共卫生问题。 1