title: Application of modern drug metabolism structure determination tools and assays to the in vitro metabolism of imiloxan.
abstract: Imiloxan is an alpha2 adrenoceptor antagonist and was developed for depression in the 1980's. In Phase 1 clinical trials imiloxan dosing led to hypersensitivity reactions; the molecule's development was discontinued. The present study revisits the in vitro metabolism of imiloxan using modern analytical methods. Human and rat liver microsomes convert imiloxan into a variety of metabolites many of which are unstable and or reactive. Imiloxan also yields high protein covalent binding in microsomal assays. Imiloxan is a useful test molecule for defining the relationship between liver covalent binding and idiosyncratic toxicity.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Roche Palo Alto LLC, Palo Alto, CA 94304, USA. bfitch@stanford.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Fitch
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Liling
authors.initials: L
authors.lastname: Liu
authors.forename: Axel
authors.initials: A
authors.lastname: Paehler
authors.forename: May
authors.initials: M
authors.lastname: Young
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000032:analysis* / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000032:analysis* / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; C044484:Imiloxan