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Modulation of hepatic cytochrome P450 activity by peptide mediators associated with inflammatory disease.

机译：与炎性疾病相关的肽介体对肝细胞色素P450活性的调节。

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摘要

As pharmacists, our primary goal is to insure that every patient receives the most effective and safe dose of a given drug. In order to achieve this goal, we must gain an understanding of alterations in drug metabolism and transport, which drive many of the pharmacokinetic phenomena associated with altered physiologic states. Cellular signaling initiated through the interaction of peptides, termed cytokines, with their receptors is believed to mediate changes in drug handling during inflammation. Only through understanding the impact of cytokines on drug metabolism and transport will it be possible to predict altered pharmacokinetics in a given patient. The studies described herein further our knowledge of the important role that cytokines play in modulating drug metabolism and transport in vivo. The initial study (Chapter IV) provides evidence that stimulation of an acute cytokine response through low dose endotoxin administration can alter the metabolism and renal transport of a probe substrate in man. Further, individual changes observed in renal transport are shown to correlate with the extent of the inflammatory cytokine response as assessed by changes in NF-κB activation in peripheral blood mononuclear cells. Studies presented in Chapters V and VI demonstrate that endogenous signaling by the inflammatory cytokine TNFα differentially modulates the induction of cytochrome P450 (P450) enzymes by the classic inducers phenobarbital and clofibrate. A recent report of elevated TNFα levels in patients with Alzheimer's disease (AD), suggests that unobserved alterations in drug pharmacokinetics may be present in AD. In order to test this hypothesis, and to provide support for future human studies, differences in P450 activity between AD transgenic mice and their wild-type mice were characterized (Chapter VII). Further studies (Chapter VIII), demonstrate that alterations in P450 activity occur gradually with age and may be mediated by elevated levels of the amyloid-beta 1-42 peptide in AD transgenic mice. In summary, the studies presented herein demonstrate that inflammation and TNFα can have profound effects on drug metabolism and disposition in vivo, which could potentially lead to altered pharmacokinetics in man. Additionally, studies in mouse models of AD, a disease associated with inflammatory cytokine alterations, suggests that P450 associated drug metabolism and drug pharmacokinetics may be altered in AD patients.
机译：作为药剂师，我们的主要目标是确保每个患者都能获得最有效，最安全的给定药物剂量。为了实现这一目标，我们必须了解药物代谢和运输的变化，这些变化驱动许多与生理状态改变相关的药代动力学现象。据信通过称为细胞因子的肽与其受体的相互作用而引发的细胞信号传导介导了炎症过程中药物处理的变化。只有了解细胞因子对药物代谢和转运的影响，才有可能预测给定患者的药代动力学变化。本文描述的研究进一步了解了细胞因子在调节体内药物代谢和运输中的重要作用。初步研究（第四章）提供了证据，证明通过低剂量内毒素刺激刺激急性细胞因子反应可以改变人体探针基质的代谢和肾脏转运。此外，如通过外周血单核细胞中NF-κB活化的变化所评估，显示在肾脏转运中观察到的个体变化与炎性细胞因子反应的程度相关。第五章和第六章中的研究表明，炎性细胞因子TNFα的内源性信号传导差异性地调节了经典诱导剂苯巴比妥和氯贝贝特对细胞色素P450（P450）酶的诱导。最近有关阿尔茨海默氏病（AD）患者的TNFα水平升高的报告表明，AD中可能存在药物药代动力学的未观察到变化。为了检验该假设并为将来的人类研究提供支持，对AD转基因小鼠与其野生型小鼠之间的P450活性进行了表征（第VII章）。进一步的研究（第VIII章）表明，P450活性的改变会随着年龄的增长而逐渐发生，并且可能是由AD转基因小鼠中β-淀粉样蛋白1-42肽水平升高所介导的。总之，本文提出的研究表明，炎症和TNFα可能对药物代谢和体内处置产生深远影响，这可能会导致人体药代动力学改变。此外，在与炎症细胞因子改变有关的疾病AD小鼠模型中的研究表明，AD患者的P450相关药物代谢和药物药代动力学可能会改变。

著录项

  • 作者

    Van Ess, Peter James.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Health Sciences Pharmacy.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 230 p.
  • 总页数 230
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药剂学;药理学;
  • 关键词

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