Placental P-gp/BCRP in fetal drug exposure and regulation by hormones/xenobiotic

胎盘 P-gp/BCRP 在胎儿药物暴露和激素/异生素调节中的作用

• 批准号: 8470410
• 负责人: QINGCHENG MAO
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8470410
• 关键词: ABCB1 gene; ABCG2 gene; Address; Affect; Age; Binding; Biological Models; Blood - brain barrier anatomy; Blood Circulation; Buprenorphine; Bupropion; Cells; Data; Dexamethasone; Diazepam; Digoxin; Drug Efflux; Drug Interactions; Drug Kinetics; Drug Regulations; Drug usage; Epidermal Growth Factor; Estradiol; Ethics; Exposure to; FVB Mouse; Fetus; Gestational Age; Glyburide; Goals; Growth Factor; HIV Protease Inhibitors; Homologous Gene; Hormones; Human; Hydrocortisone; Hypericum perforatum; Illicit Drugs; In Vitro; Instruction; Knockout Mice; Knowledge; Lead; Ligands; Liver; Measures; Mediating; Methadone; Mus; Nelfinavir; Nitrofurantoin; Non-Steroidal Anti-Inflammatory Agents; Nuclear Receptors; Omeprazole; P-Glycoprotein; Penetration; Perinatal Exposure; Pharmaceutical Preparations; Pharmacotherapy; Phenobarbital; Phenytoin; Placenta; Plasma; Pregnancy; Pregnant Women; Progesterone; Pyrenes; Regulation; Rodent; Role; Safety; Saquinavir; Small Intestines; Somatomedins; Staging; Substrate Specificity; Syncytiotrophoblast; Testing; Topotecan; Toxic effect; Tretinoin; Xenobiotics; age related; apical membrane; clinically relevant; design; drug mechanism; fetal; fetal drug exposure; human ABCG2 protein; human HGH-V protein; in vivo; in vivo Model; inhibitor/antagonist; pregnant; progesterone receptor B; trophoblast

PROJECT SUMMARY (See instructions); Illicit and licit drugs are routinely used during pregnancy without the necessary pharmacokinetics, efficacy, or safety data. P-gp and BCRP are the two major ABC efflux transporters in the placenta that limit fetal exposure to drugs. The levels of P-gp and BCRP in the placenta change with gestation; however, how the changes in transporter expression affect fetal drug exposure over gestation is still poorly understood. Thus, the goal of this project is to assess the role of placental P-gp and BCRP in fetal drug exposure over gestation and elucidate the mechanisms by which P-gp and BCRP in the placenta are regulated during pregnancy. We have shown that progesterone strongly induces BCRP in BeWo cells via progesterone receptor B (PRB). Another related and important, but yet unanswered question is whether expression and activity of placental P-gp and BCRP can be altered by exposure to drugs through inhibition or induction. We hypothesize that expression and activity of placental P-gp and BCRP change with gestation through regulation by pregnancy hormones, growth factors, and retinoic acid as well as by drugs and xenobiotics. To test these hypotheses, we propose the following specific aims. We will determine 1) the effects of drug-drug interactions on fetal exposure to a P-gp (norbuprenorphine), a BCRP (nitrofurantoin), or a dual P-gp/BCRP (bupropion) substrate in FVB mice at two different gestational ages with and without a P-gp (nelfinavir), a BCRP (pantoprazole), or a dual P-gp/BCRP (elacridar) inhibitor, respectively; 2) if/n vitro expression and activity of P-gp and BCRP in primary human trophoblasts (from early, mid, and term placenta) are altered by the treatment with PXR (e.g., HIV protease inhibitors, methadone, St John's wort, and buprenorphine), CAR (e.g., phenobarbital, phenytoin and diazepam), AhR (e.g., omeprazole and benezo[a]pyrene) or PPARy (e.g., some NSAIDs) ligands at clinically relevant plasma concentrations, and elucidate the mechanisms of changes in expression observed; 3a) if in vitro expression and activity of P-gp and BCRP in primary human trophoblasts (from early, mid, and term placenta) are regulated by pregnancy hormones (e.g., progesterone, 17|3-estradiol, Cortisol, placental growth hormone), growth factors (e.g., epidermal growth factor and insulin-like growth factors), and all-trans retinoic acid, individually and in combination, at plasma concentrations observed during pregnancy, and elucidate the mechanisms of changes in expression observed; 3b) if progesterone regulates In vivo expression and activity of placental Bcrpi through PRB. We will measure expression and in vivo activity of placental Bcrp1 in PRB-/- pregnant mice compared with those in wild-type pregnant mice.

项目总结（见说明）; 在没有必要的药代动力学、疗效或安全性数据的情况下，非法和合法药物在妊娠期间被常规使用。P-gp和BCRP是胎盘中限制胎儿暴露于药物的两种主要ABC外排转运蛋白。胎盘中P-gp和BCRP的水平随妊娠而变化;然而，转运蛋白表达的变化如何影响妊娠期胎儿药物暴露仍知之甚少。因此，本项目的目标是评估胎盘P-gp和BCRP在妊娠期间胎儿药物暴露中的作用，并阐明妊娠期间胎盘中P-gp和BCRP的调节机制。我们已经证明，黄体酮通过黄体酮受体B（PRB）强烈诱导BeWo细胞中的BCRP。另一个相关且重要但尚未回答的问题是胎盘P-gp和BCRP的表达和活性是否可以通过抑制或诱导而通过暴露于药物而改变。我们假设胎盘P-gp和BCRP的表达和活性随着妊娠的变化而变化，这是通过妊娠激素、生长因子和维甲酸以及药物和外源性物质的调节实现的。为了验证这些假设，我们提出了以下具体目标。我们将确定1）药物相互作用对胎儿暴露于P-gp的影响（去甲丁丙诺啡），一种BCRP（呋喃妥因）或双重P-gp/BCRP两种不同胎龄FVB小鼠（含和不含P-gp）中的（安非他酮）底物（奈非那韦），BCRP（泮托拉唑）或双重P-gp/BCRP（依克立达）抑制剂; 2）如果PXR治疗改变了原代人滋养层细胞（来自早期、中期和足月胎盘）中P-gp和BCRP的体外表达和活性（例如，HIV蛋白酶抑制剂、美沙酮、圣约翰草和丁丙诺啡）、CAR（例如，苯巴比妥、苯妥英和地西泮），AhR（例如，奥美拉唑和苯并[a]芘）或PPARy（例如，一些NSAID）配体，并阐明观察到的表达变化的机制; 3a）如果在原代人滋养层（来自早期、中期和足月胎盘）中P-gp和BCRP的体外表达和活性受妊娠激素（例如，孕酮，17| 3-雌二醇、皮质醇、胎盘生长激素）、生长因子（例如，表皮生长因子和胰岛素样生长因子）和全反式视黄酸，单独和组合，在妊娠期间观察到的血浆浓度，并阐明观察到的表达变化的机制; 3b）孕酮是否通过PRB调节胎盘Bcrpi的体内表达和活性。我们将测量与野生型妊娠小鼠相比，PRB-/-妊娠小鼠胎盘Bcrp 1的表达和体内活性。