ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS--MECHANISM

化学品暴露后外源性物质的肝脏处置改变 或生理变异具有药理学和毒理学 影响 抑制药物或毒性化合物的肝摄取可 延长药理活性或增强全身毒性。 同样地， 抑制代谢活化化合物的肝排泄可 延迟药理作用的发生或增加肝毒性。 目标 这项研究的目的是检查化学诱导的改变， 肝易位的有机阴离子，阐明这些机制 相互作用，并确定结构和物理化学特征 与特定肝移位过程中的扰动相关。 三种模式有机阴离子肝胆处置的扰动 底物（对乙酰氨基酚、吲哚菁绿色和丙戊酸）将 由选定的探针（苯巴比妥和丙磺舒）诱导。 一 将采用多实验方法确定研究中心， 这些扰动的机制。 探针改变的程度 底物/衍生代谢物的总体肝胆处置将 在离体灌注大鼠肝脏中定量。 探针相关 肝脏摄取和排出的改变将在孤立的 肝细胞，以及探针对参与肝细胞的过程的影响。 将在代谢试验中评估底物的肝细胞易位。 和胞质蛋白结合研究。 初步数据表明 通过探针改变对乙酰氨基酚的肝胆处置是由于 在小管部位与葡糖苷酸结合物相互作用。 到 为了验证这一假设，对乙酰氨基酚葡萄糖醛酸苷在 小管大鼠肝质膜囊泡的特征将在 探针的存在和不存在。 此外，假设， 理化性质（亲脂性、空间因子和/或pKa） 探针确定肝胆处置的扰动程度， 将使用一系列结构相关但 物理化学上不同的，每个探针的类似物。 基于此 信息，结构-肝胆转运相互作用关系 将被开发，并参与肝脏的载体的特异性 将检查模型有机阴离子的迁移。 阐明 参与有机阴离子肝转位的机制，以及 异生素相互作用如何改变这些过程的知识， 了解肝脏如何处理内源性和 外源化合物，并且是利用这些过程的先决条件， 达到理想的治疗终点。 这项工作的优点是 当人们考虑到在肝脏中发生的外源性物质的数量时， 消除，以及肝脏转运改变的可能性 这些代理人由其他药物，环境化学品，或疾病状态。

Altered hepatic disposition of xenobiotics secondary to chemical exposure or physiologic variations has both pharmacologic and toxicologic implications. Inhibition of hepatic uptake of drugs or toxic compounds may prolong pharmacologic activity or enhance systemic toxicity. Likewise, inhibition of hepatic excretion of metabolically activated compounds may delay onset of pharmacologic effect or increase hepatotoxicity. The goal of the proposed research is to examine chemical-induced alterations in the hepatic translocation of organic anions, elucidate the mechanisms of these interactions, and identify structural and physicochemical features associated with perturbations in specific hepatic translocation processes. Perturbations in hepatobiliary disposition of three model organic anion substrates (acetaminophen, indocyanine green, and valproic acid) will be induced by selected probes (phenobarbital and probenecid). A multiexperimental approach will be utilized to define the site(s) and mechanism(s) of these perturbations. The degree to which probes alter overall hepatobiliary disposition of substrates/derived metabolite(s) will be quantitated in the isolated perfused rat liver. Probe-associated alterations in hepatic uptake and egress will be characterized in isolated hepatocytes, and the effect of probes on processes involved in hepatocellular translocation of substrates will be assessed in metabolic and cytosolic protein binding studies. Preliminary data indicate that altered heptobiliary disposition of acetaminophen by the probes is due to interactions with the glucuronide conjugate at the canalicular site. To test this hypothesis, the transport of acetaminophen glucuronide in canalicular rat liver plasma membrane vesicles will be characterized in the absence and presence of probes. Furthermore, the hypothesis that physicochemical properties (lipophilicity, steric factors and/or pKa) of probes determine the extent of perturbation in hepatobiliary disposition of the substrates will be tested using a series of structurally related, but physicochemically distinct, analogs of each of the probes. Based on this information, structure-hepatobiliary transport interaction relationships will be developed, and the specificity of carriers involved in the hepatic transport of the model organic anions will be examined. Elucidation of the mechanisms involved in hepatic translocation of organic anions, and a knowledge of how xenobiotic interactions may alter these processes, is fundamental to understanding how the liver disposes of endogenous and exogenous compounds, and is a prerequisite to exploiting these 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.