Utility of DPX2 cells for predicting CYP3A induction-mediated drug-drug interactions and associated structure-activity relationships.

The increase in cytochrome P450 (P450) enzyme activity noted upon exposure to therapeutics can elicit marked drug-drug interactions (DDIs) that may ultimately result in poor clinical outcome or adverse drug effects. As such, in vitro model systems that can rapidly and accurately determine whether potential therapeutics activate the human pregnane X receptor (PXR) and thus induce CYP3A P450 levels are highly sought after tools for drug discovery. To that end, we assessed whether DPX2 cells, a HepG2-derived cell line stably integrated with a PXR expression vector plus a luciferase reporter, could detect agents that not only cause PXR activation/CYP3A induction but also elicit clinical DDIs. All 20 clinical inducers and 9 of 15 clinical noninducers examined activated PXR in DPX2 cells ( E max > 8-fold), although activation parameters obtained with the noninducers were not predictive of DDI. The relative induction score, calculated by combining PXR activation parameters (EC 50 and E max ) in DPX2 cells for seven inducers plus four noninducers with their efficacious total plasma concentrations, strongly correlated ( R 2 = 0.90) with the magnitude of induction of midazolam clearance. Thus, the DPX cell-based PXR activation system is not only capable of distinguishing potential inducers in a high-throughput manner but can also differentiate among compounds in predicting the magnitude of induction-mediated DDIs, providing a means for structure-activity relationship screening during discovery and development.