The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology

Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to 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 only from the perspective of the absorption, distribution, metabolism, and excretion 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. We use the Remote Sensing and Signaling Theory to examine the roles of DMEs and transporters in intra-tissue, inter-organ, and inter-organismal communication via metabolites and signaling molecules. This 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 and the prediction of drug toxicities based upon the interplay of these proteins with key pathways in metabolism and signaling. It 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.