Mechanisms of Drug Disposition During Pregnancy

怀孕期间的药物处置机制

基本信息

批准号：
9069781
负责人：
JASHVANT D Unadkat
金额：
$ 100.29万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069781
关键词：
ABCG2 gene Address Adult Affect Blood Circulation CYP2B6 gene CYP2D6 gene CYP3A4 gene Clinical Clinical Data Cytochrome P450 Data Diabetes Mellitus Dose Drug Design Drug Efflux Drug Kinetics Drug abuse Drug toxicity Drug usage Enzymes Exposure to Fetus Funding Gestational Age Goals Growth HIV HIV Infections HIV Protease Inhibitors Health Hepatic Hormones Hypertension Illicit Drugs Indinavir Infection Knowledge Label Light Literature Liver Maternal Exposure Mental Depression Metabolism Methadone Minerals Modeling Morbidity - disease rate Mothers Neonatal Orphan Perinatal Exposure Pharmaceutical Preparations Pharmacology Physiological Placenta Plasma Population Postpartum Period Pregnancy Pregnant Women Publishing Regimen Regulation Reporting Research Project Grants Risk Risk Factors Safety Surveys System Teratogens Testing Therapeutic United States National Institutes of Health Virus Diseases Vitamins Vulnerable Populations Xenobiotics age related base drug efficacy drug mechanism drug of abuse fetal fetal drug exposure fetus drug adverse effect illicit drug use interest maternal morbidity multidisciplinary novel pharmacokinetic model programs risk benefit ratio smoking cessation statistics

项目摘要

DESCRIPTION (provided by applicant): Illicit drug use during pregnancy is a major risk factor for maternal and fetal morbidity. In addition, licit drugs are routinely administered to pregnant women, and therefore their fetuses, without the necessary data about the pharmacokinetics of these drugs in these vulnerable populations. The overall goal of this POI is to make use of drugs during pregnancy efficacious (licit drugs) and safer (licit and illicit drugs). We will achieve thi goal by testing the following overarching and unifying central hypothesis: Expression and activity of hepatic cytochrome P450 enzymes and placental drug transporters during pregnancy are regulated by pregnancy- related hormones and/or growth factors and by exposure to drugs and xenobiotics. Elucidating these mechanisms and quantifying the pregnancy-induced changes in these CYP and transporter activities will allow PBPK prediction of changes in maternal-fetal exposure to drugs througout pregnancy. The P450 enzymes and transporters we will study are those likely to be quantitatively most important for metabolism and transport of both illicit and licit drugs in the liver or the placenta, namely CYP3A (Project 1), CYP2B6 and CYP2D6 (Project 2), P-gp and BCRP (Project 3), and OCTS, NET, and SERT (Project 4). Pregnancy is known to induce expression and activity of hepatic CYP3A and CYP2D6, thus possibly lowering maternal exposure to drugs and potentially decreasing their efficacy. In the placenta, P-gp and BCRP participate in the efflux of drugs from the fetal compartment to the maternal circulation, thus protecting the fetus from adverse effects of drugs, while 0CT3, NET and/or SERT function to allow the entry of potentially toxic drugs into the fetal circulation. Thi POI uses a collaborative, synergistic, multidisciplinary and systems pharmacology approach to test the above-stated hypothesis. Results obtained from the proposed studies will allow us to predict how maternal and fetal exposure to licit and illicit drugs is affected by pregnancy and by gestational age and will reveal interesting and potentially novel mechanisms on physiological regulation of CYPs and transporters studied.

描述（由申请人提供）：怀孕期间的非法药物使用是孕产妇和胎儿发病率的主要危险因素。此外，在这些脆弱人群中，通常会对孕妇和胎儿一起常规服用LICIT药物，因此没有有关这些药物的药代动力学的必要数据。该POI的总体目标是在怀孕期间使用药物有效（LICIT药物）和更安全（LICIT和非法药物）。我们将通过测试以下基准和统一中心假设来实现这一目标：怀孕期间肝细胞色素P450酶和胎盘药物转运蛋白的表达和活性受妊娠相关的激素和/或生长因子以及暴露于药物和黑生生物学的暴露来调节。阐明这些机制并量化这些CYP和转运蛋白活性的妊娠诱导的变化，将允许PBPK预测产妇暴露于药物的变化。我们将研究的P450酶和转运蛋白可能在肝脏或胎盘中的代谢和非法药物和胎盘中的非法和LICIT药物的运输可能是最重要的，即CYP3A（项目1），CYP2B6和CYP2D6（项目2）（项目2），P-GP和BCRP（Project 3），以及nets，nets，sert（Project 3）和Sert（Project 3），4）。已知妊娠会诱导肝CYP3A和CYP2D6的表达和活性，从而降低母体暴露于药物并可能降低其功效。在胎盘中，P-gp和BCRP参与了从胎儿区室到母体循环的药物的排出，从而保护胎儿免受药物的不良影响，而0ct3，Net和/或Sert的功能使潜在有毒药物进入胎儿循环。 Thi Poi使用协作，协同，多学科和系统药理学方法来检验上述假设。从拟议的研究中获得的结果将使我们能够预测孕妇和胎儿暴露于妊娠和胎龄如何影响，并将揭示有关CYP和研究蛋白的生理调节的有趣且潜在的新型机制。