Evaluation of Time-Dependent Cytochrome P450 Inhibition Using the Area Under the Curve Shift Method

New molecular entities (NMEs) causing time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes are a concern because they can be responsible for drug–drug interactions (DDIs). DDIs occur when one drug affects the metabolism of a coadministered drug. This changes the exposure and clearance of a coadministered drug. The consequences are a risk of therapeutic efficacy of a drug to severe adverse drug reactions, leading to death. Thus, it is very important to identify any TDI early in the drug discovery process. In this chapter, potential DDIs for NMEs are evaluated by identifying time-dependent CYP inhibitors with human liver microsomes. The area under the curve (AUC) shift method is utilized by measuring the shift in AUC of the percent activity remaining versus the inhibitor concentration plot. By producing in vitro TDI data, clinical DDI can be understood and predicted. In vitro testing helps predict in vivo results, as well as helps in the design or avoidance of clinical trials.