title: A novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition and kinetic aqueous solubility.
abstract: In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug-drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug-drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain jose.perezdelpalacio@medinaandalucia.es.
authors.forename: José
authors.initials: J
authors.lastname: Pérez
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: Caridad
authors.initials: C
authors.lastname: Díaz
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Asensio
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Palafox
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
mesh_terms: D019295:Computational Biology / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007700:Kinetics; D054852:Small Molecule Libraries; D012995:Solubility; D013379:Substrate Specificity
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D054852:Small Molecule Libraries; D051544:Cytochrome P-450 CYP3A
keywords: CYP450 inhibition; data integration; kinetic solubility