title: A comparative study of the CYP450 inhibition potential of marketed drugs using two fluorescence based assay platforms routinely used in the pharmaceutical industry.
abstract: Semi-automated high throughput screening for the inhibition of major human cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4) expressed in Escherichia Coli (Cypex bactosomes) or human lymphoblastoid cells (Gentest cDNA microsomes) using fluorescent probes has been evaluated using 68 marketed drugs. In general lower IC50 values were obtained with Cypex bactosomes compared with Gentest cDNA microsomes. This could be due to use of higherconcentration of protein and also the lower activity of Gentest cDNA microsomes. Notably, when compared with in vivo clinical drug-drug interactions (cDDIs) gathered from clinical studies reported in the scientific literature Cypex bactosome data was better at predicting in vivo cDDI. Consequently, from the data obtained in this comparative study, a fluorescence based assay using Cypex bactosomes is more suitable as a front-line screen for the prediction of potential downstream CYP450 driven cDDIs.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline S.p.A, 37135, Verona, Italy. Mahmud.kajbaf@aptuit.com
authors.forename: Mahmud
authors.initials: M
authors.lastname: Kajbaf
authors.forename: Raffaele
authors.initials: R
authors.lastname: Longhi
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
authors.forename: Federica
authors.initials: F
authors.lastname: Vinco
authors.forename: Monica
authors.initials: M
authors.lastname: Rigo
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
mesh_terms: D001331:Automation; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005453:Fluorescence; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D015335:Molecular Probes; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D013379:Substrate Specificity; D013678:Technology, Pharmaceutical / Q000379:methods*; D014162:Transfection
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D015335:Molecular Probes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System