Mechanisms of Drug Disposition During Pregnancy

怀孕期间的药物处置机制

• 批准号: 8415301
• 负责人: JASHVANT D Unadkat
• 金额: $ 82.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8415301
• 关键词: 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 Factor; 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; 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; interest; multidisciplinary; neonatal morbidity; novel; pharmacokinetic model; programs; risk benefit ratio; smoking cessation; statistics

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）：怀孕期间使用非法药物是孕产妇和胎儿发病的主要危险因素。此外，合法药物通常是给孕妇使用的，因此她们的胎儿没有这些药物在这些脆弱人群中的药代动力学的必要数据。《行动纲领》的总目标是使怀孕期间有效使用药物（合法药物）和更安全（合法和非法药物）。我们将通过测试以下总体和统一的中心假设来实现这一目标：妊娠期间肝细胞色素P450酶和胎盘药物转运蛋白的表达和活性受妊娠相关激素和/或生长因子以及暴露于药物和外源性药物的调节。阐明这些机制并量化这些CYP和转运体活性的妊娠引起的变化，将使PBPK能够预测整个妊娠期间母体-胎儿药物暴露的变化。我们将研究的P450酶和转运体是那些在肝脏或胎盘中非法和合法药物的代谢和运输中可能在定量上最重要的酶和转运体，即CYP3A（项目1）、CYP2B6和CYP2D6（项目2）、P-gp和BCRP（项目3），以及OCTS、NET和SERT（项目4）。已知妊娠可诱导肝脏CYP3A和CYP2D6的表达和活性，从而可能降低母体对药物的暴露，并可能降低其疗效。在胎盘中，P-gp和BCRP参与药物从胎室向母体循环的外排，从而保护胎儿免受药物的不良影响，而0CT3、NET和/或SERT功能允许潜在毒性药物进入胎儿循环。该POI采用协作、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合法和非法药物是如何受到怀孕和胎龄的影响的，并将揭示所研究的CYPs和转运体生理调节的有趣和潜在的新机制。