Pharmacogenomics of 4-hydroxycoumarin anticoagulants.
Oral anticoagulants of the 4-hydroxycoumarin class, typified by warfarin, are used worldwide to treat thromboembolic disease. These drugs show the beneficial attributes of high efficacy and low cost, but patient management can be complicated by their narrow therapeutic index and wide inter-individual variability in dosing. Our understanding of the latter complication has improved significantly in recent years due to intense investigation of genetic factors influencing drug pharmacokinetics (CYP2C9) and pharmacodynamic response (VKORC1). In particular, the discovery of polymorphisms in the VKORC1 gene that strongly impact oral anticoagulant dose has heightened expectations that genetic testing for a relatively small cadre of warfarin-response genes might substantially enhance patient care in this area, especially during the initiation phase of therapy. However, enthusiasm for genotype-based dosing of oral anticoagulants must be balanced against the ready availability of both a simple phenotypic test (prothrombin time) and an antidote to over-anticoagulation (vitamin K). Wide-spread acceptance of genetically based tests for establishing therapy with warfarin and its congeners will likely require additional evidence that such an approach offers protection against a variety of negative anticoagulation outcomes, especially severe bleeding, as well as offering utility across many racial populations. This article will review recent events in these and other related areas.
Au
Nicholas
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Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA.
Rettie
Allan E
AE
D015110:4-Hydroxycoumarins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D017850:Economics, Pharmaceutical; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D010641:Phenotype; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship; D064417:Vitamin K Epoxide Reductases
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases