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

Abstract

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.

Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3

“…Our findings that gut-derived metabolites were increased in the serum of both the Oat1 KO and Oat3 KO micetogether with our demonstration that some are ligands in vitro, provides additional support for the importance of these transporters in regulating communication between the host and commensal organisms. Altogether, our results align with the Remote Sensing and Signaling Theory, which proposes that drug transporters and drug metabolizing enzymes participate in inter-organ and interorganismal communication through the transport and modification of small molecules to maintain homeostasis (62,63). Thus, it is critical to understand the gamut of endogenous physiological functions of drug transporters systemically and locally.…”

Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease

“…Upon entering the blood through oral or parenteral routes, they are frequently taken up by the liver, where they may be modified by drug metabolizing enzymes (DMEs). The unmodified and modified drugs are generally eliminated into urine after kidney uptake or into the bile via the hepatobiliary system [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Uremic Toxins in Organ Crosstalk

“…The Remote Sensing and Signaling Theory is a general theory that attempts to explain how multi-specific, oligo-specific, and monospecific transporters and enzymes work together, along with regulatory proteins (e.g., nuclear receptors, kinases) to achieve optimal levels of hundreds if not thousands of small molecules in different body tissues (e.g., CNS, kidney, liver, placenta) and body fluids [e.g., blood, CSF, urine, bile, amniotic fluid; (43)(44)(45)]. In such a multi-scale complex adaptive system, it is hard to posit a single orchestrator, for this is likely an emergent property of many interacting transporters, enzymes, nuclear receptors, metabolites, and signaling molecules-in many interacting organs and organisms.…”