Figure 1:

A) The Remote Sensing and Signaling System (Network) mediates inter-organ and inter-organismal communication through small molecules with “high informational content.” In healthy and diseased states, endogenous and other small molecules with key roles in metabolism, signaling and maintaining redox state are mediators of remote communication between organs. Important axes--like the brain-gut and gut-liver-kidney axes--are characterized by sets of transporters, enzymes and regulatory proteins (e.g., nuclear receptors) in each organ. Often, these multi-specific, oligo-specific and mono-specific proteins are dynamically regulated at the apical and basolateral surfaces of polarized epithelial tissues--thereby providing many combinatorial possibilities for regulating net flux between tissues, body fluids, and other interfaces. Small molecule communication mediated by transporters, enzymes and regulatory proteins of the Remote Sensing and Signaling System (Network) also occurs at the inter-organismal level, as in the case of mother-fetus and host-gut microbiome. For example, the gut microbiome-derived small molecules play important metabolic and signaling roles in the host through the activity of transporters, enzymes and other proteins of the Remote Sensing and Signaling System in the intestine, liver, kidney, brain and other remote tissues. B) The ADME system overlaps largely or completely with the greater Remote Sensing and Signaling System. The Remote Sensing and Signaling System consists of hundreds of proteins, including multi-specific, oligo-specific, and mono-specific transporter and enzymes. Within a subset of these proteins exists the ADME system, which includes what are often termed “drug” transporters and “drug” metabolizing enzymes. These systems exist simultaneously and have overlapping functionality, with drugs potentially perturbing the Remote Sensing and Signaling System. The ADME system likely also contains some proteins that are independent of the Remote Sensing and Signaling System.