Stereospecific Metabolism of R- and S-Warfarin by Human Hepatic Cytosolic Reductases
Autor: | Grover P. Miller, Linda P. Desrochers, Dustyn A. Barnette, Robert Nshimiyimana, Dakota L. Pouncey, Bryce P. Johnson, Thomas E. Goodwin |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Pharmaceutical Science Stereoisomerism Alcohol Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Therapeutic index Cytosol medicine Humans heterocyclic compounds cardiovascular diseases Chromatography High Pressure Liquid chemistry.chemical_classification Warfarin Anticoagulants Metabolism Articles Kinetics 030104 developmental biology Enzyme chemistry Biochemistry Liver Enantiomer Oxidoreductases medicine.drug |
Popis: | Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world; however, its clinical use is often challenging because of its narrow therapeutic range and interindividual 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 have suffered from coelution of pairs of alcohol metabolites; thus, those studies have not established 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 per minute, Km 0.67 mM) was reduced more efficiently than S-warfarin (Vmax 27 pmol/mg per minute, 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. |
Databáze: | OpenAIRE |
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