Pharmacogenetics of warfarin: current status and future challenges.
Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P(450) 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.
Wadelius
M
M
Department of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden. mia.wadelius@medsci.uu.se
Pirmohamed
M
M
D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; 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