The future prospects of pharmacogenetics in oral anticoagulation therapy.
Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy.
Kamali
Farhad
F
Wolfson Unit of Clinical Pharmacology, School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne. farhad.kamali@ncl.ac.uk
Pirmohamed
Munir
M
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004032:Diet; D005544:Forecasting; D005820:Genetic Testing; D006801:Humans; D010597:Pharmacogenetics / Q000639:trends*; D011110:Polymorphism, Genetic / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D014812:Vitamin K / Q000008:administration & dosage; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases