特异性药物性肝损伤的药代动力学和毒物动力学概念。

IF 3.9 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Expert Opinion on Drug Metabolism & Toxicology Pub Date : 2022-07-01 Epub Date: 2022-08-24 DOI:10.1080/17425255.2022.2113379
Robert A Roth, Omar Kana, David Filipovic, Patricia E Ganey
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引用次数: 0

摘要

导言:特发性药物性肝损伤(IDILI)会导致患者发病和死亡,并减少有效药物的使用。与取决于剂量的内在毒性反应不同,IDILI 只发生在少数治疗剂量的患者身上。关于药物暴露、作用方式和肝损伤之间的因果关系,还有很多未知因素。因此,有关 IDILI 发病机制的假说层出不穷:讨论当前 IDILI 病因假说所依据的药代动力学和毒效学特征,并以图表说明:解释IDILI病因的假说都涉及药代动力学的改变,这种改变导致血浆药物浓度上升到毒性阈值以上,或者涉及毒效学的改变,这种改变导致毒性阈值降低。例如,药物代谢或转运体多态性的改变会引起药物动力学的改变。药物引起的线粒体损伤、有毒内源性因子的积累或有害的免疫反应都可能导致毒性阈值降低。新开发的交互式免费软件(DemoTox-PK; https://bit.ly/DemoTox-PK)可以让用户直观地了解这些改变是如何导致毒性反应的。这些图示为特异性反应的概念化提供了一个框架,并可促进未来有关 IDILI 作用模式的讨论、教育和研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Pharmacokinetic and toxicodynamic concepts in idiosyncratic, drug-induced liver injury.

Introduction: Idiosyncratic drug-induced liver injury (IDILI) causes morbidity and mortality in patients and leads to curtailed use of efficacious pharmaceuticals. Unlike intrinsically toxic reactions, which depend on dose, IDILI occurs in a minority of patients at therapeutic doses. Much remains unknown about causal links among drug exposure, a mode of action, and liver injury. Consequently, numerous hypotheses about IDILI pathogenesis have arisen.

Areas covered: Pharmacokinetic and toxicodynamic characteristics underlying current hypotheses of IDILI etiology are discussed and illustrated graphically.

Expert opinion: Hypotheses to explain IDILI etiology all involve alterations in pharmacokinetics, which lead to plasma drug concentrations that rise above a threshold for toxicity, or in toxicodynamics, which result in a lowering of the toxicity threshold. Altered pharmacokinetics arise, for example, from changes in drug metabolism or from transporter polymorphisms. A lowered toxicity threshold can arise from drug-induced mitochondrial injury, accumulation of toxic endogenous factors or harmful immune responses. Newly developed, interactive freeware (DemoTox-PK; https://bit.ly/DemoTox-PK) allows the user to visualize how such alterations might lead to a toxic reaction. The illustrations presented provide a framework for conceptualizing idiosyncratic reactions and could serve as a stimulus for future discussion, education, and research into modes of action of IDILI.

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来源期刊
Expert Opinion on Drug Metabolism & Toxicology
Expert Opinion on Drug Metabolism & Toxicology 医学-生化与分子生物学
CiteScore
7.90
自引率
2.30%
发文量
62
审稿时长
4-8 weeks
期刊介绍: Expert Opinion on Drug Metabolism & Toxicology (ISSN 1742-5255 [print], 1744-7607 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on all aspects of ADME-Tox. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering metabolic, pharmacokinetic and toxicological issues relating to specific drugs, drug-drug interactions, drug classes or their use in specific populations; issues relating to enzymes involved in the metabolism, disposition and excretion of drugs; techniques involved in the study of drug metabolism and toxicology; novel technologies for obtaining ADME-Tox data. Drug Evaluations reviewing the clinical, toxicological and pharmacokinetic data on a particular drug. The audience consists of scientists and managers in the pharmaceutical industry, pharmacologists, clinical toxicologists and related professionals.
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