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.

Public Health Relevance

OVERALL PROGRAM NARRATIVE Use of marijuana amongst pregnant women in the US is increasing, and a major concern is the transfer of cannabinoids across the placental barrier, leading to placental (and therefore fetal) toxicity. Studies proposed in this P01 will elucidate how and to what extent the maternal-placental-fetal exposure to cannabinoids is altered during pregnancy and how to predict these changes. Completion of these studies will significantly advance our ability to predict the risks of using marijuana during pregnancy (a significant public health problem that cannot be addressed using the traditional approach of conducting a clinical trial ) and have the potential to reveal strategies to minimize such risks.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1)
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Rapaka, Rao
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University of Washington
Schools of Pharmacy
United States
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Han, Lyrialle W; Gao, Chunying; Mao, Qingcheng (2018) An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 14:817-829
Patilea-Vrana, Gabriela I; Unadkat, Jashvant D (2018) When Does the Rate-Determining Step in the Hepatic Clearance of a Drug Switch from Sinusoidal Uptake to All Hepatobiliary Clearances? Implications for Predicting Drug-Drug Interactions. Drug Metab Dispos 46:1487-1496
Kumar, Vineet; Yin, Jia; Billington, Sarah et al. (2018) The Importance of Incorporating OCT2 Plasma Membrane Expression and Membrane Potential in IVIVE of Metformin Renal Secretory Clearance. Drug Metab Dispos 46:1441-1445
Neradugomma, Naveen K; Drafton, Kaitlyn; O'Day, Diana R et al. (2018) Marijuana use differentially affects cannabinoid receptor expression in early gestational human endometrium and placenta. Placenta 66:36-39
Liao, Michael Z; Gao, Chunying; Phillips, Brian R et al. (2018) Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation. Drug Metab Dispos 46:100-108
Guo, Yingying; Chu, Xiaoyan; Parrott, Neil J et al. (2018) Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clin Pharmacol Ther 104:865-889
Johnson, Emily J; González-Peréz, Vanessa; Tian, Dan-Dan et al. (2018) Selection of Priority Natural Products for Evaluation as Potential Precipitants of Natural Product-Drug Interactions: A NaPDI Center Recommended Approach. Drug Metab Dispos 46:1046-1052
Grant, Kimberly S; Petroff, Rebekah; Isoherranen, Nina et al. (2018) Cannabis use during pregnancy: Pharmacokinetics and effects on child development. Pharmacol Ther 182:133-151
Wagner, David J; Shireman, Laura M; Ahn, Sojung et al. (2018) Disposition of Methamphetamine and Major Metabolites in Mice: Role of Organic Cation Transporter 3 in Tissue-Selective Accumulation of Para-Hydroxymethamphetamine. Drug Metab Dispos 46:1277-1284
Zhang, Zufei; Imperial, Marjorie Z; Patilea-Vrana, Gabriela I et al. (2017) Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses. Drug Metab Dispos 45:920-938

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