Beyond CAR and PXR.

It is becoming increasingly evident that constitutive, induced, and regulated expression of genes important to the drug disposition process such as drug transporters, phase I and II metabolic enzymes are largely under the transcriptional control of certain nuclear receptor (NR) family members. In the past decade, important new insights regarding the role and relevance of ligand-activated nuclear receptors such as such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in terms of their activation by endogenous biochemicals, natural products, as well as synthetic compounds have led to a much better understanding of the xenobiotic-mediated induction process and the clinical relevance of such NRs to drug therapy in general. However, in addition to CAR and PXR, many orphan and adopted orphan NRs have recently been identified as key regulators of drug disposition genes. Indeed, nuclear receptors including farnesoid X receptor, peroxisome proliferator-activated receptor, and hepatocyte nuclear factors (1alpha, 3 and 4alpha) exhibit overlapping ligand specificities and regulate multiple gene targets, resulting in tissue- and organ-specific expression of drug disposition genes. In this review, the biology, pathophysiology, and the potential clinical relevance of such NRs to drug disposition and response are discussed.