A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism?

Pregnane X receptor (PXR, NR112) is a xenobiotic receptor whose primary function is to regulate the expression of drug-metabolizing enzymes (DMEs) and drug transporters. Drug-induced PXR activation and subsequent enzyme and transporter induction has been proposed to be an important mechanism for the drug-drug interactions. In addition to activating PXR, many pharmaceutical chemicals can also function as reversible or irreversible inhibitors of DMEs, which may also impact the pharmacokinetics and pharmacodynamics (PK/PD) of drugs. Therefore, we cannot simply conclude that the PXR-induced alteration in enzyme expression always reflects functional changes. We should consider both PXR activation and DMEs inhibition to improve drug safety in the clinic.