A novel screening method for cytochrome P450 induction in early drug discovery using advanced biomimetic chromatography targeting the pregnane X receptor

One of the main reasons for drug development failure is pharmacokinetics, specifically, the risk that Cytochrome P450 (CYP) induction potential may prevent drugs from achieving their expected efficacy due to a reduction in the blood concentration of concomitant drugs or the drug itself. It is therefore desirable to select compounds with a low induction potential, but HepaRG cell and Other in vitro induction assays are not sufficient to evaluate induction potential due to throughput and evaluation system limitation. We therefore evaluated the predictivity of CYP induction using advanced biomimetic chromatography (aBMC) that applies biomimetic chromatography for assessing affinity to the pregnane X receptor (PXR). We prepared a PXR-immobilized column for the first time, and evaluated its performance in terms of immobilized efficiency, stability, and recovery ratio of the number of eluted to injected test compounds. Investigation of 42 different compounds including both CYP induction-positive and -negative compounds, suggested that the retention time difference (ΔRT) between the PXR and reference columns obtained from aBMC was significantly more related to CYP induction than LogD and LogK (HSA), which indicate affinity for albumin, and has practical predictivity for judging CYP induction (74 % accuracy, 83 % sensitivity, 67 % precision). This novel prediction method is expected to improve the quality of drug candidates and the probability of successful drug development.

ADMET screening; Advanced biomimetic chromatography; CYP induction; PXR.