TY - JOUR T1 - The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-Androstene-3,17-dione JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2367 LP - 2374 DO - 10.1124/dmd.109.028183 VL - 37 IS - 12 AU - Leen Lootens AU - Peter Van Eenoo AU - Philip Meuleman AU - Geert Leroux-Roels AU - Frans T. Delbeke Y1 - 2009/12/01 UR - http://dmd.aspetjournals.org/content/37/12/2367.abstract N2 - The metabolism in primary human hepatocyte cultures often deviates from that in clinical studies, which in turn are hampered by ethical constraints. Here the use of urokinase-type plasminogen activator-severe combined immunodeficiency [uPA(+/+)-SCID] mice transplanted with human hepatocytes was investigated as a model for in vivo metabolic studies. The urinary excretion profile after oral administration of 4-androstene-3,17-dione (AD) in chimeric mice was investigated by using gas chromatography-mass spectrometry detection and was compared with previously reported metabolites of AD in humans and cell cultures. Chimeric mice exhibited an AD metabolic profile similar to that of humans, showing androsterone and etiocholanolone as major metabolites. Several hydroxylated steroids were detected as minor metabolites in the chimeric mice compared with hepatocyte cultures. A significant correlation between the extent of liver replacement and the relative abundances of human-type metabolites was established. The results for AD showed that humanized liver uPA-SCID mice can serve as an alternative model for in vivo metabolism studies in humans. In the future, this model could possibly be used for other steroids or pharmaceutical compounds.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics ER -