ALTERED HEPATIC DISPOSITION OF ANIONIC DRUGS--MECHANISM

外源性物质继发于化学暴露后肝脏处置的改变 或者生理变异既有药理学的，也有毒理学的 这意味着什么。抑制肝脏对药物或有毒化合物的摄取可能 延长药理活性或增强全身毒性。同样， 抑制代谢活性化合物的肝脏排泄可能 延缓药理作用起效或增加肝毒性。目标是 这项拟议的研究的目的是检查化学物质在体内诱导的变化 有机阴离子在肝脏的转运，阐明其机制 相互作用，并确定结构和物理化学特征 与特定肝脏移位过程中的扰动有关。 三种模型有机阴离子在肝胆配置中的微扰 底物(扑热息痛、吲哚青绿和丙戊酸) 由选定的探针(苯巴比妥和丙磺舒)诱导。一个 将使用多实验方法来确定场地(S)和 这些扰动的机制(S)。探测器更改的程度 底物/衍生代谢物的总体肝胆处置(S) 在离体灌流的大鼠肝脏中进行定量。与探测关联 肝脏摄取和排出的改变将是孤立的 肝细胞，以及探针对参与的过程的影响。 底物的肝细胞转位将在代谢中进行评估 以及胞质蛋白结合研究。初步数据显示， 探针改变对乙酰氨基酚的肝胆管处置是由于 与小管部位的葡萄糖醛酸偶联物相互作用。至 检验这一假说，对乙酰氨基酚葡萄糖醛酸苷在体内的转运 小管大鼠肝细胞质膜囊泡的特征 探头的存在和缺失。此外，假设 其理化性质(亲脂性、立体因子和/或pKA) 探针测定肝胆系膜上皮细胞的微扰程度 基板将使用一系列结构上相关的测试，但 物理化学上不同的，每个探针的类似物。在此基础上 信息、结构-肝胆转运相互作用关系 会发展，而携带者的特异性参与了肝脏 我们将考察模型中有机阴离子的传输。澄清： 参与肝脏有机阴离子转运的机制，以及一个 关于外来生物相互作用如何改变这些过程的知识，是 了解肝脏如何处理内源性和 外源化合物，是利用这些过程的先决条件 达到理想的治疗终点。这项工作的价值在于 当人们考虑到经历肝脏的外来生物的数量时，就会意识到 消除，以及在肝脏转运中发生改变的可能性 这些药物由其他药物、环境化学品或疾病状态引起。

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.