ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS--MECHANISMS

继发于药物的阴离子药物对肝脏的影响 相互作用、化学物质暴露或生理变化 药理学和毒理学的含义。口服药物 生物利用度，以及药物活性的持续时间， 可能会因肝脏移位的改变而发生实质性的改变 毒品的问题。同样，肝脏摄取或排泄 外源生物可能会增加全身或肝脏的毒性。长的- 这项研究计划的学期目标仍然是 发展了一种对微扰如何在 肝脏转运系统影响整体肝胆倾向 阴离子药物。一种利用隔离的多实验方法 正常和运输缺陷突变Wistar的肝脏灌流 大鼠，以及大鼠肝小管质膜囊泡 被用来检验假设：(L)模型有机阴离子 对乙酰氨基酚葡萄糖醛酸通过胆汁中的 运河生电有机阴离子转运体(CEOAT) 而不是管状多特异性有机阴离子转运体 (CMOAT)，和(2)探针(苯巴比妥、丙磺舒和/或 代谢物)通过改变cEOAT底物的肝胆配置 竞争性抑制胆汁排泄，而探针不能 抑制胆汁中cMOAT底物的排泄。一名员工的能力 维持肝细胞极性和胆汁的体外模型系统 小管功能预测探头相关改变的临床研究 将评估肝胆底物的处置情况。这款车 系统可能成为研究肝胆的重要工具 药物处置，因为它允许直接进入肝细胞和 邻近胆道间隔，最大限度地减少实验性胆管的使用 动物，适用于健康或患病的人类 肝细胞。关于肝脏III期的机制信息 戒毒是有限的。对涉及的机制的阐明 有机阴离子在肝脏的转运，以及如何进行的知识 外生生物的相互作用改变了这些过程，是 了解肝脏如何处理内源性和外源性 化合物。这些信息将有助于先验预测 外源物质和代谢物在肝脏中的处置 改变肝脏的运输，是开发肝脏的先决条件 运输过程以达到理想的治疗终点。这个 这项工作的价值是当人们考虑到 经过肝脏消除的外源生物，以及可能 其他药物对这些药物的肝脏转运的改变， 环境化学物质，或疾病状态。

Altered hepatic disposition of anionic drugs secondary to drug interactions, chemical exposure, or physiologic variations has pharmacologic and toxicologic implications. Oral drug bioavailability, as well as the duration of pharmacologic activity, may be altered substantially by changes in the hepatic translocation of drugs. Likewise, impaired hepatic uptake or excretion of xenobiotics may enhance systemic or hepatic toxicity. The long- term objective of this research program continues to be the development of a mechanistic understanding of how perturbations in hepatic transport systems influence overall hepatobiliary disposition of anionic drugs. A multiexperimental approach utilizing isolated perfused livers from normal and transport-deficient mutant Wistar rats, as well as rat canalicular liver plasma membrane vesicles, will be employed to test the hypotheses that: (l) the model organic anion acetaminophen glucuronide is transported into bile via the canalicular electrogenic organic anion transporter (cEOAT) rather than the canalicular multispecific organic anion transporter (cMOAT), and (2) probes (phenobarbital, probenecid, and/or metabolites) alter hepatobiliary disposition of cEOAT substrates by competitive inhibition of biliary excretion, whereas probes do not inhibit the biliary excretion of cMOAT substrates. The ability of an in vitro model system that maintains hepatocyte polarity and bile canalicular function to predict probe-associated alterations in hepatobiliary substrate disposition will be evaluated. This model system may become an important tool for studying hepatobiliary drug disposition as it allows direct access to the hepatocyte and adjacent biliary compartment, minimizes the use of experimental animals, and can be applied to healthy or diseased human hepatocytes. Mechanistic information regarding hepatic Phase III detoxification is limited. Elucidation of the mechanisms involved in hepatic translocation of organic anions, and knowledge of how xendbiotic interactions alter these processes, is fundamental to understanding how the liver disposes of endogenous and exogenous compounds. This information will facilitate a priori predictions of hepatic disposition of xenobiotics and metabolites in response to altered hepatic transport, and is prerequisite to exploiting hepatic transport processes to achieve desirable therapeutic endpoints. The merit of this work is realized when one considers the number of xenobiotics that undergo hepatic elimination, and the potential for alterations in hepatic transport of these agents by other drugs, environmental chemicals, or disease states.