RT Journal Article SR Electronic T1 In Vitro Metabolism of Irosustat, a Novel Steroid Sulphatase Inhibitor: Inter-Species Comparison, Metabolite Identification and Metabolic Enzyme Identification JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.111.038315 DO 10.1124/dmd.111.038315 A1 Veronica Ventura A1 Josep Sola A1 Carles Celma A1 Concepcion Peraire A1 Rosendo Obach YR 2011 UL http://dmd.aspetjournals.org/content/early/2011/04/04/dmd.111.038315.abstract AB Irosustat is a novel steroid sulphatase inhibitor for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulphamate which undergoes de-sulphamoylation in aqueous solution yielding the sulphamoyl-free derivative, 667-Coumarin. The aim of the present work was to study the in vitro metabolism of Irosustat including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites and of the enzymes participating in its metabolism. Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey and humans (both sexes). In liver microsomes, the dog appeared as the species that metabolized Irosustat most similarly to humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to Irosustat metabolism. Various mono-hydroxylated metabolites of Irosustat and of 667-Coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10 and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulphatase. The main metabolites formed by hepatocytes were glucuronide and sulphate conjugates of 667-Coumarin and of some of its mono-hydroxylated metabolites. The major P450 enzymes involved in the transformation of Irosustat were: CYP2C8, CYP2C9, CYP3A4/5 and CYP2E1. Moreover, various phase II enzymes (UGTs and SULTs) were capable of conjugating many of the metabolites of Irosustat and 667-Coumarin, however, the clinically relevant isoforms could not be elucidated.