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Giving the importance of drug transporters in the absorption, distribution, and excretion of a diverse array of environmental toxins and clinically important drugs, alteration in the function of these transporters plays a critical role in intra‐ and inter‐individual variability of the therapeutic efficacy and the toxicity of the drugs. As a result, the activity of drug transporters must be under tight regulation so as to carry out their normal duties. Key players involved in the regulation of transporters are hormones, protein kinases, nuclear receptors, scaffolding proteins, and disease conditions. These players may affect transporter activity at multiple levels, including (i) when and how often a gene encoding a given transporter is transcribed (transcriptional control), (ii) how the primary RNA transcript is spliced or processed (RNA processing control), (iii) which mRNA in the cytoplasm is translated by ribosomes (translational control), (iv) which mRNA is destabilized in the cytoplasm (mRNA degradation control), and (v) how a transporter is modified and assembled after it has been made (posttranslational control). Post‐translational modification may alter physical and chemical properties of the transporters, their folding, conformation, distribution, stability, and their activity. Because of such loops and layers of regulation, the functional diversity of these transporters often far exceeds the considerable molecular diversity of the transporter genes, which may help in utilizing identical transporter proteins for different cellular functions in different cell types.

Regulation of transporter activity at the gene level usually occurs within hours and days and is therefore classified as long‐term or chronic regulation. Long‐term regulation usually occurs when the body undergoes massive change, such as during development or the occurrence of disease. Regulation at the posttranslational level usually occurs within minutes or hours and is therefore classified as short‐term or acute regulation. Short‐term regulation usually occurs when the body has to deal with rapidly changing amounts of substances as a consequence of variable intake of drugs, fluids, or meals, as well as metabolic activity.

The overlapping substrate specificities among different transporters or different isoforms of the same transporter, their wide tissue distributions, and the various types of regulation of expression and function, mediated by signaling molecules secreted from remote tissues into the body fluids, contribute to the complicated communication network. Hormones and growth factors produced and released from the original organ under the internal and external stimuli arrive at the target organ and regulate the transporters in the target organ. Such networks contribute to intercellular and inter‐organ communication. This communication between cells, as well as between organs, regulates local and whole‐body homeostasis of endogenous substrates.