Common Approaches of Cytochrome P450 (CYP) Induction Assays

Abstract

The induction of enzymes is a defensive mechanism for some xenobiotics, but it may alter the drug's safety and efficacy by altering the activity of metabolic enzymes. One of the major families of enzymes involved in phase I metabolism is Cytochrome P450 (CYP) enzymes which may get induced by certain drugs. Concomitant administration of drugs due to chronic disease or polypharmacy, inducers among them may cause toxicity or reduce the plasma concentration at a sub-therapeutic level. This is one of the dangerous types of drug-drug interactions, but predictable & preventable. The CYPs get induced by three nuclear receptors, including the aryl hydrocarbon receptor (AhR); constitutive androstane receptor (CAR); the pregnane X receptor (PXR). Without identification during drug development, enzyme induction phenomenon of a new drug molecule may get noticed only during pharmacovigilance. Though, this CYP induction may not be a barrier for drug development, it may cause possible DDI and treatment failure. According to FDA guidelines, pharmaceutical industries adopted In-vitro, Ex-vivo and In-vivo techniques based on different developmental stages. The results are also interpreted based on regulatory bodies guidelines. For In-vitro assay best accepted method is using primary hepatocytes either fresh or cryopreserved, for Ex-vivo liver slices of different species and in-vivo, clinical investigations are the extreme option. This paper reviews current industry approaches of CYP induction assays to evaluate potentiality for a new drug molecule as an inducer.