Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In vitro Metabolism of Imiloxan.
ABSTRACT Imiloxan is an alpha(2) 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.