METABOLISM OF ANTHRACYCLINES IN THE HEPATOCYTE

蒽环类抗生素代表了一类强大的抗肿瘤药物。 临床证明有效的治疗各种白血病的药物 和实体瘤。蒽环类药物展示并延长了半衰期 循环，肝脏是它们被消除的主要部位。 肝脏排泄功能受损的情况会导致 对特定剂量的寄主毒性；此外，由于对 由蒽环类药物进入或分泌的途径 肝细胞，目前存在的技术不能有效地 预测肝脏清除蒽环类物质的能力，也不是 临床调理有合理的药理基础 在肝功能受损的情况下进行养生。这方面的研究 建议旨在阐明肝细胞的药代动力学。 在使用分离肝细胞模型的蒽环类药物中， 放射性标记阿霉素探针与高压液相色谱 代谢物形成的分析。这些研究将分析这些元素 阿霉素向肝细胞转运的动力学研究 药物流入，运输路线的结构特异性，对 阳离子配体的运输，细胞外pH，细胞能量储存， 巯基敏感膜蛋白与微管和微丝 功能。阿霉素和柔红霉素的细胞内代谢将 评估，并在细胞内积累和分布 将对阿霉素、柔红霉素及其代谢物进行分析和相关 对药物进入细胞的速度等因素， 动物的营养状态及微粒体诱导剂的作用 酶的代谢。药物和代谢物的外排将同时进行评估 在没有和存在荷尔蒙外流诱导剂的情况下理解 这些药物的排泄机制；诸如相对速率等因素 阿霉素及其代谢物的外排及其可能的相互作用 阿霉素及其衍生物之间的相互作用将会退出细胞 学习。其他抗肿瘤药物对运输的贡献， 蒽环类药物及其代谢物的代谢和排泄 被评估。此外，涌入和流入之间的动态关系， 蒽环类药物的积累、区隔、代谢和外流 将通过计算机网络热力学建模进行分析。

The anthracycline antibiotics represent a powerful class of antineoplastic drugs with proven clinical utility in the treatment of various leukemias and solid tumors. The anthracyclines exhibit and extended half-life in the circulation, with the liver being a primary site for their elimination. Conditions of compromised hepatic excretory function result in increased host toxicity for a given dose; furthermore, since little is known of the pathways utilized by the anthracyclines for entry into or secretion from the liver cell, techniques presently in existence do not effectively predict the capacity of the liver to eliminate the anthracyclines, nor is there a rational pharmacologic basis for modification of the clinical regimen in the face of compromised hepatic function. The research in this proposal is directed at elucidation of the hepatocellular pharmacokinetics of the anthracyclines utilizing the isolated hepatocyte model, a radiolabeled adriamycin probe and high pressure liquid chromatographic analysis of metabolite formation. These studies will analyze the elements of adriamycin transport into the hepatocyte in terms of the kinetics of drug influx, structural specificity of the transport route, dependence of transport on cationic ligands, extracellular pH, cellular energy stores, sulfhydryl sensitive membrane proteins and microtubular and microfilament function. Intracellular metabolism of adriamycin and daunorubicin will be assessed, and the intracellular accumulation and distribution of adriamycin, daunorubicin and their metabolites will be analyzed and related to such factors as the rate of drug transport into the cell, the nutritional state of the animal and the effects of inducers of microsomal enzyme metabolism. Efflux of drug and metabolites will be evaluated both in the absence and presence of hormonal inducers of efflux to understand the excretory mechanism for these drugs; such factors as the relative rates of efflux of adriamycin and its metabolites and the possible interaction between adriamycin and its derivatives in exit from the cell will be studied. The contribution of other antineoplastic drugs to transport, metabolism and excretion of the anthracyclines and their metabolites will be evaluated. In addition, the dynamic relationship between influx, accumulation, compartmentation, metabolism and efflux of the anthracyclines will be analyzed by computer network thermodynamic modeling.