title: Assays and applications in warfarin metabolism: what we know, how we know it and what we need to know.
abstract: BACKGROUND
  Coumadin (R/S-warfarin) is the most widely prescribed oral anticoagulant in the world; nevertheless, its clinical use is complicated by unpredictability in dose requirements to achieve and maintain optimal anticoagulation. Variations in warfarin metabolism among patients contribute to unpredictability in therapeutic responses. Studying the clinical relevance of warfarin metabolism poses a significant analytical challenge. Warfarin is given to patients as an equal mixture of R and S enantiomers. Both drugs undergo extensive metabolism through different pathways to generate > 20 structurally similar isomeric metabolites.
  
  
  METHODS
  The article discusses how analytical methods have evolved to effectively resolve and quantify individual metabolites. The authors also discuss how the application of these methods has identified clinically relevant metabolic pathways for warfarin and fostered the investigation of clinical biomarkers for patient responses to therapy. The article additionally presents the power of these methods and how aspects of warfarin metabolism have led to the use of warfarin as a phenotyping probe for multiple drug metabolizing enzymes.
  
  
  CONCLUSIONS
  Progress in these areas has been hampered by shortcomings in analytical methods and a narrow focus on one metabolic pathway. Recent advances in liquid chromatographic-mass spectral methods can rapidly analyze most warfarin metabolites. It is now possible to effectively assess alternate metabolic pathways and expand biomarker analyses for clinical and phenotyping applications.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 516, Little Rock, AR 72205, USA.
authors.forename: Drew R
authors.initials: DR
authors.lastname: Jones
authors.forename: Grover P
authors.initials: GP
authors.lastname: Miller
mesh_terms: D000925:Anticoagulants / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D002849:Chromatography, Gas; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D010641:Phenotype; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase