RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 2367
OP 2374
DO 10.1124/dmd.109.028183
VO 37
IS 12
A1 Lootens, Leen
A1 Van Eenoo, Peter
A1 Meuleman, Philip
A1 Leroux-Roels, Geert
A1 Delbeke, Frans T.
YR 2009
UL http://dmd.aspetjournals.org/content/37/12/2367.abstract
AB 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