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It is now time to fully\u00a0rethink 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)\u00a0of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies\u2014including systems biology analyses of \u201comics\u201d data as well as metabolomics studies\u2014indicate 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\u00a0proteins in a large multiorgan remote sensing and signaling\u00a0network.\u00a0We use the Remote Sensing and Signaling Theory (RSST)\u00a0to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST\u2010based\u00a0view 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\u00a0proteins with key pathways in metabolism and signaling. The RSST\u2010based view\u00a0should 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.<\/jats:p>","DOI":"10.1002\/cpt.1818","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T15:35:55Z","timestamp":1583163355000},"page":"40-53","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology"],"prefix":"10.1111","volume":"108","author":[{"given":"Sanjay K.","family":"Nigam","sequence":"first","affiliation":[{"name":"Departments of Pediatrics and Medicine School of Medicine University of California, San Diego La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin T.","family":"Bush","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Medicine School of Medicine University of 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