Author(s)

José Pérez, Caridad Díaz, Irene G. Salado, Daniel I. Pérez, Fernando Peláez, Olga Genilloud, Francisca Vicente

Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Fundación Centro de Excelencia, Investigación de Medicamentos Innovadores de Andalucía, Granada, Spain.
Instituto de Química Médica, Madrid, Spain.

It is a common practice in drug discovery organizations to screen new chemical entities in order to predict future drug-drug interactions. For this purpose, there are two main assay strategies, one based on recombinant cytochrome P450 (rCYP) enzymes and fluorescent detection, and other on human liver microsomes (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 aqueous kinetic solubility may play in this lack of correlation. We found that drug discovery compounds with unacceptable kinetic solubility, measured by a turbidimetric solutibility assay, tended to yield higher IC₅₀ values in in vitro models based on human liver microsomes, whereas compounds with kinetic solubility values higher than 50 μM showed very similar IC₅₀ 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.

CYP Inhibition; Fluorogenic Substrates; Drug Safety; Human Liver Microsomes; Drug-Drug Interactions

Pérez, J. , Díaz, C. , Salado, I. , Pérez, D. , Peláez, F. , Genilloud, O. and Vicente, F. (2013) Evaluation of the effect of compound aqueous solubility in cytochrome P450 inhibition assays. Advances in Bioscience and Biotechnology, 4, 628-639. doi: 10.4236/abb.2013.45083.