Mechanism of altered vectoral hepatic excretion

描述（由申请人提供）：了解药物吸收， 分布、代谢和排泄（ADME）对于发育至关重要。 安全有效的药物治疗此外，了解机制， 药物间相互作用影响药物ADME对于鉴别 药物制剂的潜在毒性或副作用。 具体来说，这项工作旨在将微粒体诱导剂对 药物缀合物的肝排泄对肝药物转运蛋白的调节 负责I相产生的药物缀合物的排泄， II代谢。这项工作将决定是否改变矢量 对乙酰氨基酚（APAP）代谢产物从肝胆到 用苯巴比妥型微粒体诱导剂预处理肝血管， 由于有机阴离子转运蛋白MRP 2和MRP 3的肝水平的变化， mrp3。因此，具体目标1和2将决定肝脏是否 治疗后MRP 2和/或MRP 3的水平和/或分布发生改变 与组成型活性受体（CAR）诱导剂，如果这些变化与 APAP-葡萄糖醛酸苷、APAP-硫酸盐和APAP-GSH的排泄增加， 肝脏进入血液。接下来，具体的aim 3将决定APAP是否 代谢物是MRP 2和MRP 3的底物，使用制备的膜囊泡 来自异源表达mrp 2或mrp 3的Sf 9细胞。最后，具体目标3 将确定PB是否通过核转位增加mrp 3 mRNA， CAR和启动子区中推定的PB应答元件的激活， 大鼠MRP 3.这些研究将阐明控制肝脏的机制， 药物的运输和排泄，并将有助于开发 更安全更有效的药物制剂。

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.