In Vitro CYP Induction Using Human Hepatocytes

Induction potential of compounds towards CYP1A2, 2B6 and 3A4 via the aryl hydrocarbon (AhR), constitutive androstane (CAR), and pregnane X (PXR) nuclear receptors (NRs), respectively, is routinely determined during small molecule drug development. Significant CYP induction can result in therapeutic failure from clinical exposure of a compound outside the therapeutic window, if the respective enzymes are responsible for a significant portion of the drugs overall metabolism and clearance. Co-medications can also be impacted in a similar manner. Additionally, if metabolism via the induced CYP enzyme results in toxic or pharmacologically active compounds being produced, exaggerated pharmacological effects may be seen resulting in direct and/or indirect toxicity. The following chapter will describe methodologies used for determining CYP induction using isolated human hepatocytes, the current gold standard for such in vitro assays. Where appropriate in the chapter recent guidelines will be highlighted by regulatory agencies, such as, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA).