Drug disposition in pathophysiological conditions.
Drug disposition in pathophysiological conditions.
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DOI：
10.2174/138920012803341302
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发表时间：
2012-11
影响因子：
2.3
通讯作者：
Ghose R
中科院分区：
文献类型：
--
作者：
Gandhi A;Moorthy B;Ghose R
几种关键药物代谢酶 (DME) 和转运蛋白的表达和活性在各种病理生理条件下发生改变，导致药物代谢和处置的改变。这可能会导致药物反应的个体差异，从而对广泛使用的临床相关药物的安全性和有效性产生深远的影响。这篇综述文章重点介绍了炎症和传染病以及癌症、肥胖/糖尿病、脂肪肝疾病、心血管疾病和类风湿关节炎等常见疾病中药物配置的改变。许多临床相关药物的治疗指数较窄。因此，这些药物的处置方式的任何改变都可能导致功效降低和毒性增加。还讨论了 DME 和转运蛋白的变化对临床相关药物的药代动力学/药效学的影响。已知炎症介导的促炎细胞因子的释放和 Toll 样受体 (TLR) 的激活在 DME 和转运蛋白的下调中发挥重要作用。尽管发生这种情况的机制尚不清楚，但一些研究表明，炎症相关的细胞信号传导途径及其与基础转录因子和核受体在 DME 和转运蛋白调节中的相互作用在药物代谢改变中发挥着重要作用。在多种疾病状态下改变 DME 和转运蛋白的调节将有助于未来开发强大的体外和体内工具来预测药物反应并选择更好的药物设计和开发。目的是促进更好地理解病理生理条件下 DME 和转运蛋白调节的机制细节。
Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses. This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity. The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying the regulation of DMEs and transporters in pathophysiological conditions.
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影响因子：
3.7
作者：
Baker SS;Baker RD;Liu W;Nowak NJ;Zhu L
通讯作者：
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DOI：
10.1124/jpet.104.075374
发表时间：
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