TY - JOUR T1 - Stereospecific Metabolism of R- and S-Warfarin by Human Hepatic Cytosolic Reductases JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.075929 SP - dmd.117.075929 AU - Dustyn A Barnette AU - Bryce Johnson AU - Dakota L Pouncey AU - Robert Nshimiyimana AU - Linda Desrochers AU - Thomas E Goodwin AU - Grover Paul Miller Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/06/20/dmd.117.075929.abstract N2 - Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world, yet its clinical use is often challenging due to a narrow therapeutic range and inter-individual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction of each warfarin enantiomer yields two warfarin alcohol isomers, and the corresponding four alcohols retain varying levels of anticoagulant activity. Studies on the kinetics of warfarin reduction have often lacked resolution of parent drug enantiomers and suffered from co-elution of pairs of alcohol metabolites; thus, those studies fail to establish the importance of individual, stereospecific reductive pathways. We report the first steady-state analysis of R- and S-warfarin reduction in vitro by pooled human liver cytosol. As determined by authentic standards, the major metabolites were 9R,11S-warfarin alcohol for R-warfarin, and 9S,11S-warfarin alcohol for S-warfarin. R-warfarin (Vmax 150 pmol/mg/min, Km 0.67 mM) was reduced more efficiently than S-warfarin (Vmax 27 pmol/mg/min, Km 1.7 mM). Based on inhibitor phenotyping, carbonyl reductase-1 dominated R-and S-warfarin reduction followed by aldo-keto reductase-1C3 and then other members of that family. Overall, the carbonyl at position 11 undergoes stereospecific reduction by multiple enzymes to form the S alcohol for both drug enantiomers, yet R-warfarin undergoes reduction preferentially. This knowledge will aid in assessing the relative importance of reductive pathways for R- and S-warfarin and factors influencing levels of pharmacologically active parent drugs and metabolites thus impacting patient dose-responses. ER -