title: Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms.
abstract: Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide. There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9*2 and *3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement. Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations. Using relevant genotypes to calculate starting dose may improve safety during the initiation period. Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials. One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation.
authors: Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. a.k.daly@ncl.ac.uk
authors: Ann K
authors: AK
authors: Daly
mesh_terms: D000465:Algorithms; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D001777:Blood Coagulation / Q000187:drug effects*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D044469:Racial Groups / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; D064417:Vitamin K Epoxide Reductases