Positioning Enzyme- and Transporter-Based Precipitant Drug-Drug Interaction Studies in Drug Design

In vitro assessment of the potential of compounds to affect drug metabolizing enzymes and transporters and perpetrate drug-drug interactions (DDIs) is a common practice in drug research. For the development phase, regulators define an exhaustive list of enzymes and transporters to consider, but DDIs associated with many of these are minor and can be well-managed in the clinic; thus, progression of drug candidates that address unmet medical needs should not be curtailed due to this property. However, some enzymes and transporters are very important in drug disposition, so it is important to avoid/reduce inhibition or induction of these through drug design. Herein, simplified criteria and methodologies amenable to high-throughput screening are defined to enable drug design to address DDI risk. A strategy is proposed that focuses on the most important enzymes and transporters: namely, cytochrome P450 (CYP) 3A4, CYP2C9, and CYP2D6, organic anion transporting polypeptide (OATP) 1B1, and breast cancer resistant protein (BCRP).