Glucuronidation of Monohydroxylated Warfarin Metabolites by Human Liver Microsomes and Human Recombinant UDP-Glucuronosyltransferases

• DOI: 10.1124/jpet.107.129858
• Publication Date: 2007-10-06T00:25:56Z
• Authors: Agnieszka Zielinska; Cheryl F. Lichti; Stacie Bratton; Neil C. Mitchell; Anna Gallus-Zawada; Vi-Huyen Le; Moshe Finel; Grover P. Miller; Anna Radominska-P...; Jeffery H. Moran
• Keywords: Human liver

Our understanding of human phase II metabolic pathways which facilitate detoxification and excretion warfarin (Coumadin) is limited. The goal this study was to test the hypothesis that there are specific hepatic extrahepatic UDP-glucuronosyltransferase (UGT) isozymes, responsible for conjugating hydroxylated metabolites warfarin. Glucuronidation activity liver microsomes (HLMs) eight recombinant UGTs toward (<i>R</i>)- (<i>S</i>)-warfarin, racemic warfarin, major cytochrome P450 (4′-, 6-, 7-, 8-, 10-hydroxywarfarin) has been assessed. HLMs, UGT1A1, 1A8, 1A9, 1A10 showed glucuronidation 4′-, and/or 8-hydroxywarfarin with <i>K</i>_m values ranging from 59 480 μM <i>V</i>_max 0.03 0.78 μM/min/mg protein. Tandem mass spectrometry studies structure comparisons suggested occurring at C4′-, C6-, C7-, C8-positions. Of UGT isozymes tested, UGT1A9 exclusively metabolized 8-hydroxywarfarin, whereas UGT1A1 8-hydroxywarfarin. Studies isoforms UGT1A8 7- UGT1A10 glucuronidated UGT1A4, 1A6, 1A7, 2B7 did not have any substrate, none evaluated catalyzed reactions or 10-hydroxywarfarin. This first identifying characterizing glucuronidate similar rates known be associated metabolism. Continued characterization these may enhance our ability reduce life-threatening costly complications therapy.