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Título

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

Autor Pérez, José; Díaz, Caridad; Salado, Irene G. ; Perez, Daniel I.; Peláez, Fernando; Genilloud, Olga; Vicente, Francisca
Palabras clave CYP Inhibition
Fluorogenic Substrates
Drug Safety
Human Liver Microsomes
Drug-Drug Interactions
Fecha de publicación 2013
EditorScientific Research Publishing
Citación Advances in Bioscience and Biotechnology 4: 628- 639 (2013)
ResumenIt 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
URI http://hdl.handle.net/10261/99668
Identificadoresissn: 2156-8456
e-issn: 2156-8502
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