ABSTRACT
Changes in the expression of absorption, distribution, metabolism and excretion (ADME) genes can impact the pharmacokinetics (PK) of many small molecule drugs. Regulation of the expression of these genes can occur at the level of transcription, translation, mRNA stability, and protein stability. The most common and well-studied of these is altered transcription through the activation of a trio of receptors the aryl hydrocarbon receptor (AHR), the constitutive androstane receptor (CAR), and the pregnane X receptor (PXR). Activation of these receptors leads to an increase in transcription of their target genes (Table 17.1) and increased protein concentrations in the cell. In the case of enzyme induction, the most common consequence is a decrease in exposure of drugs that are substrates of 468the induced enzyme. Induction of transporters can result in an increase or decrease in absorption for uptake and efflux transporters, respectively, and may also alter the intracellular concentrations of their substrates. Most commonly, the site of this response is in the liver and GI tract, but response at the lungs and blood brain barrier are also important for understanding systemic ADME implications. AHR is expressed ubiquitously, while expression of CAR and PXR is generally restricted to the liver and GI tract. 1 For the purposes of this chapter, the term “xenobiotic receptors” will refer to AHR, CAR, and PXR. Other receptors will be discussed but their role in regulating ADME genes is limited compared to the xenobiotic receptors.
