Mechanism of altered vectoral hepatic excretion

描述(申请人提供)：了解药物吸收， 分布、代谢和排泄(ADME)是发育所必需的 安全有效的药物疗法。此外，理解通过哪些机制 药物-药物相互作用影响药物ADME也是识别 药物制剂的潜在毒性或副作用。 具体地说，这项工作试图将微粒体诱导剂对 药物的肝排泄与肝脏药物转运蛋白的调节 对第一阶段和第二阶段产生的药物结合物的排泄负责 II代谢。这项工作将确定向量上的变化是否 对乙酰氨基酚(APAP)代谢物从肝胆到胆汁的排泄途径 用苯巴比妥类微粒体诱导剂预处理肝血管 由于肝脏有机阴离子转运体mrp2和mrp2水平的变化 Mrp3。因此，特异性目标1和2将决定肝脏 治疗后mrp2和/或mrp3的水平和/或分布发生改变 与构成活性受体(CAR)诱导剂的关系以及这些变化是否与 随着APAP-葡萄糖醛酸脂、APAP-硫酸盐和APAP-GSH的排泄增加 将肝脏注入血液。接下来，特定的AIM3将决定APAP是否 代谢产物是mrp2和mrp3的底物，使用制备的膜囊 来自异源表达mrp2或mrp3的Sf9细胞。最后，具体目标3 将确定PB是否通过核转位增加mrp3mRNA CAR和启动子区一个可能的PB反应元件的激活 大鼠mrp3。这些研究将阐明控制肝脏的机制 药物的运输和排泄，并将有助于发展 更安全、更生物有效的药物制剂。

DESCRIPTION (provided by applicant): Understanding drug absorption, distribution, metabolism, and excretion (ADME) is essential for the development of safe, effective drug therapies. Moreover, understanding mechanisms by which drug-drug interactions affect drug ADME is also critical for identifying potential toxicities or side effects of pharmaceutical preparations. Specifically, this work seeks to relate the effects of microsomal inducers on hepatic excretion of drug conjugates to regulation of hepatic drug transporters responsible for the excretion of drug conjugates that result from phase I and II metabolism. This work will determine whether alteration in the vectoral route of excretion of acetaminophen (APAP) metabolites from hepatobiliary to hepatovascular by pretreatment with Phenobarbital-type microsomal inducers is due to changes in hepatic levels of the organic anion transporters mrp2 and mrp3. Therefore, specific aims 1 and 2 will determine whether hepatic levels/and or distribution of mrp2 and/or mrp3 is altered following treatment with constitutive active receptor (CAR) inducers and if these changes correlate with increased excretion of APAP-glucuronide, APAP-sulfate, and APAP-GSH from the liver into the blood. Next, specific aim3 will determine whether APAP metabolites are substrates for mrp2 and mrp3 using membrane vesicles prepared from Sf9 cells that heterologously express mrp2 or mrp3. Lastly, specific aim 3 will determine whether PB increases mrp3 mRNA through nuclear translocation of CAR and activation of a putative PB response element in the promoter region for rat mrp3. These studies will elucidate mechanisms that control hepatic transport and excretion of pharmaceuticals and will aid in the development of safer more biologically effective drug preparations.