Stereospecific Metabolism of R- and S-Warfarin by Human Hepatic Cytosolic Reductases

• DOI: 10.1124/dmd.117.075929
• Publication Date: 2017-06-24T00:55:30Z
• Authors: Dustyn A. Barnette; Bryce P. Johnson; Dakota L. Pouncey; Robert Nshimiyimana; Linda P. Desrochers; Thomas E. Goodwin; Grover P. Miller
• Keywords: Stereospecificity

Coumadin (rac-warfarin) is the most commonly used anticoagulant in world; however, its clinical use often challenging because of narrow therapeutic range and interindividual variations response. A critical contributor to uncertainty variability warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction each enantiomer yields two alcohol isomers, corresponding four alcohols retain varying levels activity. Studies on kinetics reduction have lacked resolution parent-drug enantiomers suffered from coelution pairs metabolites; thus, those studies not established importance individual stereospecific We report first steady-state analysis <i>R</i>- <i>S</i>-warfarin vitro by pooled human liver cytosol. As determined authentic standards, major metabolites were 9R,11S-warfarin for <i>R</i>-warfarin 9S,11S-warfarin <i>S</i>-warfarin. (<i>V</i>_max 150 pmol/mg per minute, <i>K</i>_m 0.67 mM) was reduced more efficiently than 27 1.7 mM). Based inhibitor phenotyping, carbonyl reductase-1 dominated <i>R</i>-and reduction, followed aldo-keto reductase-1C3 then other members that family. Overall, at position 11 undergoes multiple enzymes form <i>S</i> both drug enantiomers, yet preferentially. This knowledge will aid assessing relative pathways factors influencing pharmacologically active parent drugs metabolites, thus impacting patient dose responses.