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.

中文翻译：

---

药物代谢酶和转运蛋白的系统生物学：与定量系统药理学的相关性。

定量系统药理学（QSP）已成为药物发现和开发中的变革性科学。现在是时候在QSP模型的框架内重新考虑药物代谢酶（DME）和转运蛋白的生物学功能了。通常从药物的吸收，分布，代谢和排泄（ADME）的角度考虑大量DME和转运蛋白基因。但是，关于二甲醚和转运蛋白的内源性生理的数据越来越多。最近的研究（包括对“组学”数据的系统生物学分析以及代谢组学研究）表明，这些酶和转运蛋白通常是肝脏，肾脏和肠等组织中表达最高的基因之一，在基础生物学中起着协调的作用。流程。在大型的多器官遥感和信号网络中，多特异性DME和转运蛋白与寡特异性和单特异性ADME蛋白协同工作。我们使用遥感和信号理论（RSST）来检查DME和转运蛋白在组织内，器官间和生物间通过代谢物和信号分子进行的通讯中的作用。基于RSST的视图适用于胆汁酸，尿酸，类花生酸，脂肪酸，尿毒症毒素和肠道微生物组产品，以及其他具有生理意义的小有机分子。在QSP中扎根DME和转运蛋白的更广阔视野，可能有助于增进对基础生物学，基于生理学的药代动力学的理解，并基于这些ADME蛋白与代谢和信号转导的关键途径之间的相互作用来预测药物毒性。基于RSST的观点还应该在肾脏疾病，肝病，代谢综合症和糖尿病的背景下启用更具针对性的药物治疗。我们将通过系统生理学的角度进一步讨论该修订后的观点对药物和法规的影响。