title: Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition.
abstract: 1. Carbamazepine is an antiepileptic drug which is metabolized by CYP3A4 into carbamazepine-10,11-epoxide. This metabolite is then detoxified by epoxide hydrolase. As carbamazepine-10,11-epoxide has been associated with neurotoxicity, it is critical to identify whether a new antiepileptic drug has the potential to inhibit epoxide hydrolase and therefore increase carbamazepine-10,11-epoxide plasma levels. 2. In this study, an in vitro assay was developed to evaluate epoxide hydrolase activity by using carbamazepine-10,11-epoxide as probe substrate. The ability of this assay to predict drug-drug interactions (DDI) at the epoxide hydrolase level was also investigated. 3. To this aim, known inhibitors of epoxide hydrolase for which in vivo data are available were used. Firstly, carbamazepine-10,11-epoxide hydrolase activity was determined in liver microsomes, cytosol and hepatocytes. Thereafter, the IC50of epoxide hydrolase inhibitors (progabide, valproic acid, valpromide and valnoctamide) was determined in liver microsomes and hepatocytes. Finally, prediction of AUC increase was performed using the in vitro data generated. 4. Interestingly, epoxide hydrolase activity was found to be much higher in human hepatocytes compared to liver microsomes/cytosol. Even though assessed on a limited number of compounds, this study demonstrated that the use of hepatocytes seems to be a more relevant model to assess and predict DDI at the epoxide hydrolase level.
authors.affiliation: a UCB Biopharma SPRL, Non-Clinical Development , Braine-L'alleud , Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosa
authors.affiliation: a UCB Biopharma SPRL, Non-Clinical Development , Braine-L'alleud , Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnaillie
authors.affiliation: a UCB Biopharma SPRL, Non-Clinical Development , Braine-L'alleud , Belgium.
authors.forename: Hugues
authors.initials: H
authors.lastname: Chanteux
mesh_terms: D001681:Biological Assay; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D002220:Carbamazepine; D004851:Epoxide Hydrolases; C012227:carbamazepine epoxide
keywords: DDI; enzyme inhibition; epoxide hydrolase