Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2‐methoxyestradiol

The aim of this study was to characterize the metabolic pathways of 2‐methoxyestradiol (2ME2), an investigational anticancer drug. In vitro metabolism studies were performed by incubation of 2ME2 with human liver microsomes under various conditions and metabolite identification was performed using liquid chromatography‐tandem mass spectrometry. In microsomal mixtures, four major oxidative metabolites and two glucuronic acid conjugates were observed originating from 2ME2. Human liver S9 protein fraction was used to screen for in vitro sulfation but no prominent conjugates were observed. The total hepatic clearance as estimated using the well‐stirred model was approximately 712 mL/min. In vivo metabolism, assessed using 24‐h collections of urine from cancer patients treated with 2ME2 revealed that <0.01% of the total administered dose of 2ME2 is excreted unchanged in urine and about 1% excreted as glucuronides. Collectively, this suggests that glucuronidation and subsequent urinary excretion are elimination pathways for 2ME2. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1821-1831, 2007