title: Cytochrome P450 (CYP) inhibition screening: comparison of three tests.
abstract: There are several different experimental systems for screening of in vitro inhibitory potency of drugs under development. In this study we compared three different types of cytochrome P450 (CYP) inhibition tests: the traditional single substrate assays, the fluorescent probe method with recombinant human CYPs, and a novel n-in-one technique. All major hepatic drug-metabolizing CYPs were included (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4). Six compounds (sotalol, propranolol, citalopram, fluoxetine, oxazepam and diazepam) were selected for detailed comparisons. The IC50 values of each of these compounds were measured using the three assay types. The inhibitory potencies of these model drugs were generally within the same order of magnitude and followed similar inhibition profiles in all the assay types. Clinically observed inhibitory interactions, or lack thereof, were predictable with all three assays. Comparison of potencies of 'diagnostic' inhibitors revealed also some notable differences between the assays, especially regarding CYP2E1. The potency of inhibitors towards CYP3A4 was dependent on the substrate and reaction measured. Generally all three assays gave reasonably comparable results, although some unexplained differences were also noted.
authors.affiliation: Department of Pharmacology and Toxicology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland. miia.turpeinen@oulu.fi
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Laura E
authors.initials: LE
authors.lastname: Korhonen
authors.forename: Ari
authors.initials: A
authors.lastname: Tolonen
authors.forename: Jouko
authors.initials: J
authors.lastname: Uusitalo
authors.forename: Risto
authors.initials: R
authors.lastname: Juvonen
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
mesh_terms: D015283:Citalopram / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003975:Diazepam / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D010076:Oxazepam / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D015283:Citalopram; D010076:Oxazepam; D011433:Propranolol; D013015:Sotalol; D003975:Diazepam