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首页> 外文期刊>Clinical Pharmacology and Therapeutics >The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology
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The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology

机译：药物代谢酶和运输工具的系统生物学：与定量系统药理学的相关性

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摘要

Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully?rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME)?of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies—including systems biology analyses of “omics” data as well as metabolomics studies—indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME?proteins in a large multiorgan remote sensing and signaling?network.?We use the Remote Sensing and Signaling Theory (RSST)?to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST‐based?view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME?proteins with key pathways in metabolism and signaling. The RSST‐based view?should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.
机译：定量系统药理（QSP）已成为药物发现和发展中的转型性科学。现在是时候充分了？重新思考药物代谢酶（DMES）和运输函数在QSP模型的框架内的生物学功能。从吸收，分布，代谢和排泄（ADME）的角度来看，通常考虑大量的DME和转运蛋白基因？药物。然而，关于DMES和运输扣的内源性生理学存在越来越多的数据。最近的研究 - 包括“OMICS”数据以及代谢组学研究的系统生物学分析 - 表明这些酶和转运蛋白通常在肝脏，肾和肠道等组织中最高表达的基因中，具有基本生物学的协调作用流程。多特异性DMES和运输司机与寡头特异性和单特异性Adme？蛋白质在大型多地遥感和信令？网络中。？我们使用遥感和信令理论（RSST）？检查DMES和运输工具在Intratissue，Interorans中的角色，通过代谢物和信号分子进行内联通信。这种基于RSST的植物？观点适用于胆汁酸，尿酸，七氰烷，脂肪酸，尿毒症毒素和肠道微生物组产品，以及其他小有机物质的生理兴趣分子。 QSP内的DMES和运输司机的更广泛的视角可以促进对基本生物学，生理基础的药代动力学的理解，以及基于这些ADME的相互作用的药物毒性预测，其具有代谢和信号传导的关键途径。基于RSST的景观？还应该在肾病，肝病，代谢综合征和糖尿病的设置中实现更量身定制的药物疗法。我们进一步通过系统生理学的镜片讨论了该修订观点的药物和监管影响。

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    Nigam Sanjay K.; Bush Kevin T.; Bhatnagar Vibha; Poloyac Samuel M.; Momper Jeremiah D.;

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    Departments of Pediatrics and MedicineUniversity of California San DiegoLa Jolla California USA;

    Departments of Pediatrics and MedicineUniversity of California San DiegoLa Jolla California USA;

    Department of Family Medicine and Public HealthUniversity of California San DiegoLa Jolla;

    Department of Pharmaceutical SciencesUniversity of PittsburghPittsburgh Pennsylvania USA;

    Division of Pharmaceutical SciencesUniversity of California San DiegoLa Jolla California USA;

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  • 正文语种 eng
  • 中图分类 药理学;
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