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The role of transporters in the absorption, distribution, metabolism and excretion (ADME) of orally administered drugs.

机译：转运蛋白在口服药物吸收，分布，代谢和排泄（ADME）中的作用。

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摘要

Over the last two decades drug tranporter proteins have been the focus of increased study to determine their roles in drug pharmacokinetics and pharmacodynamics. Their importance is increasingly recognized by regulatory agencies, the drug development industry, and the medical community. Although a great deal of progress has been made in the field, the finer nuances and full range of transporter influence and function is still an important area of investigation.My dissertation research investigated the role of transporters on drug ADME properties in a variety of systems, including stably transfected cells, isolated rat and human hepatocytes, the isolated perfused rat liver (IPRL) system, isolated rat jejunal segments, and a human clinical study. Transfected cells and the IPRL system were used to examine the ability of the Organic Anion Transporting Polypeptides (OATP/Oatp) to efflux drugs out of cells with inconclusive results. Transfected cells and isolated rat jejunal segments were used to study the interplay of the Breast Cancer Resistance Protein (BCRP/Bcrp) with intestinal drug metabolizing enzymes, again with inconclusive results. Transfected cells and isolated rat and human hepatocytes were used to determine whether or not warfarin or phenytoin are substrates for hepatic uptake transporters. Significant inhibition of warfarin uptake by the OATP/Oatp inhibitor rifampin was seen, but further studies with OATP1B1 and OATP2B1-expressing cells indicated that neither of these isoforms are responsible for warfarin uptake. No inhibitable uptake of phenytoin was seen in hepatocytes or in transfected cells. A human clinical study was conducted to determine the effect of hepatic OATP inhibition on warfarin pharmacokinetics with the result that OATP inhibition did not increase warfarin plasma levels as would be expected if hepatic OATP uptake was an important factor in warfarin disposition. Transfected cells were used to explore possible transporter-based mechanisms for the drug-drug interactions seen between raltegravir and immunosuppressants. The experiments indicated that while this was an unlikely mechanism for the specific interactions seen, raltegravir did interact significantly with hepatic uptake and efflux transporters.
机译：在过去的二十年中，药物转运蛋白一直是增加研究的重点，以确定它们在药物药代动力学和药效学中的作用。监管机构，药物开发行业和医学界日益认识到它们的重要性。尽管在该领域已取得了很大的进步，但细微的差别以及转运蛋白的影响和功能的全面范围仍然是一个重要的研究领域。我的论文研究了转运蛋白在各种系统中对药物ADME性质的作用，包括稳定转染的细胞，分离的大鼠和人类肝细胞，分离的灌注大鼠肝脏（IPRL）系统，分离的大鼠空肠段以及人类临床研究。转染的细胞和IPRL系统用于检查有机阴离子转运多肽（OATP / Oatp）从细胞外排药物的能力，结果尚无定论。转染的细胞和分离的大鼠空肠段用于研究乳腺癌抗性蛋白（BCRP / Bcrp）与肠道药物代谢酶之间的相互作用，但结果尚无定论。使用转染的细胞以及分离的大鼠和人类肝细胞来确定华法令或苯妥英钠是否是肝摄取转运蛋白的底物。观察到OATP / Oatp抑制剂利福平对华法林摄取有显着抑制作用，但对表达OATP1B1和OATP2B1的细胞进行的进一步研究表明，这些同工型均与华法林摄取无关。在肝细胞或转染的细胞中未观察到苯妥英的抑制摄取。进行了一项人类临床研究，以确定肝OATP抑制对华法林药代动力学的影响，结果表明，如果肝OATP摄取是影响华法林治疗的重要因素，那么抑制OATP不会增加华法林的血浆水平。转染的细胞被用于探索可能的基于转运蛋白的机制，用于raltegravir和免疫抑制剂之间的药物相互作用。实验表明，尽管这对于观察到的特定相互作用而言是一种不太可能的机制，但拉格列韦确实与肝吸收和外排转运蛋白发生了显着相互作用。

著录项

  • 作者

    Shugarts, Sarah B.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 252 p.
  • 总页数 252
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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