The effects of cytochrome P450 induction by xenobiotics on endobiotic metabolism in pre-clinical safety studies

The induction of hepatic cytochrome P450 (CYP) enzymes, conjugating enzymes, and drug transporters involved in the phase I–III metabolism of xenobiotics is frequently encountered in pre-clinical drug safety studies. As xenobiotics, new drug entities can serve as ligands to three major nuclear receptors; the aryl hydrocarbon receptor (AhR), the constitutive androstane receptor (CAR), and the pregnane X receptor (PXR). These act as xenosensors that often coordinate gene expression with several other nuclear receptors normally involved in endobiotic metabolism. A subsequent gene activation cascade can result in altered liver weights and histopathology and, in some cases, reduced therapeutic efficacy if the drug under test is also a substrate for the induced metabolic enzymes. In humans, CYP induction can result in therapeutic failure for autoinducers or drug–drug interactions if the pharmacokinetic and pharmacodynamic properties of co-administered drugs are altered because they are substrates for the induced...