Evaluation of the effect of compound aqueous solubility in cytochrome P450 inhibition assays

Abstract

It is a common practice in drug discovery organiza-tions to screen new chemical entities in order to pre-dict future drug-drug interactions. For this purpose, there are two main assay strategies, one based on re-combinant cytochrome P450 (rCYP) enzymes and fluorescent detection, and other on human liver mi-crosomes (HLM) and liquid chromatography coupled to mass spectrometry. Many authors have reported a poor correlation between both technologies, giving rise to concerns about the usefulness of fluorometric methods for predicting drug-drug interactions. In this study, we investigated the role that compound aque-ous kinetic solubility may play in this lack of correla-tion. We found that drug discovery compounds with unacceptable kinetic solubility, measured by a tur-bidimetric solutibility assay, tended to yield higher IC 50 values in in vitro models based on human liver microsomes, whereas compounds with kinetic solubility values higher than 50 µM showed very similar IC 50 values in both in vitro models. Our results show that the turbidimetric solubility assay is a useful tool to identify those discovery compounds that may require further investigation in order to avoid overlooking future drug-drug interactions.