TITLE:
Evaluation of the effect of compound aqueous solubility in cytochrome P450 inhibition assays
AUTHORS:
José Pérez, Caridad Díaz, Irene G. Salado, Daniel I. Pérez, Fernando Peláez, Olga Genilloud, Francisca Vicente
KEYWORDS:
CYP Inhibition; Fluorogenic Substrates; Drug Safety; Human Liver Microsomes; Drug-Drug Interactions
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.5,
May
30,
2013
ABSTRACT: 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.