Oral anticoagulants are high-performance drugs prescribed for venous thrombosis, pulmonary embolism, in relation to ciliary arrhythmia and following heart valve transplants, myocardial infarctions and embolic complications. Detection of individual sensitivities to commonly prescribed anticoagulants – warfarin, acenocoumarol and phenprocoumon – at initial prescription of these drugs is important as correct dosage can vary seven-fold according to genotype. The therapeutic range is narrow and a small excess of the drug can cause adverse reactions, with bleeding complications being the principal danger.
The main biotransformation enzyme of oral anticoagulants is an isozyme of cytochrome P4502C9 (CYP2C9). CYP2C9 gene activity has a wide range within a population and includes extensive metabolizers, intermediate metabolizers and poor metabolizers. Three alleles of this gene differing in activity level are found in the European population:
• Wild type allele of CYP2C9*1 is characterised by normal catalytic reactivity of the enzyme.
• Allele CYP2C9*2 with polymorphism +430C>T (8-19% of European population) is characterized by low catalytic reactivity.
• Allele CYP2C9*3 with polymorphism +1075A>C (5-16% of European population) is characterized by very low catalytic reactivity.
Alleles CYP2C9*2 and CYP2C9*3 lead to poor metabolism which is associated with:
• Higher concentrations of anticoagulants in the blood.
• Lesser degradation of these drugs.
• Increased risk of hypocoagulation and haemorrhages.
• Lower therapeutic drug dosage.
CYP2C9 also takes part in biotransformation of some loop diuretics and blocking agents of angiotonin II receptors. Therefore, patients with mutations in alleles of the CYP2C9 gene can have adverse reactions following certain drug treatments.
Another gene whose polymorphism influences sensitivity to oral anticoagulants is VKORC1, encoding the subunit of vitamin K epoxide reductase complex, the target of oral anticoagulants. The promoter region of this gene contains a polymorphism, -1639G/A, which influences the level of expression. The A allele lowers the level of protein expression, which means that patients with genotype -1639AA should receive a lower dose of warfarin while patients with genotype -1639GG require a higher dose.
1. Stehle S, Kirchheiner J, Lazar A, Fuhr U. ‘Pharmacogenetics of oral anticoagulants: a basis for dose individualization’. Clin Pharmacokinet, 2008, 47(9), 565–94.
The frequency of VKORC1 -1639GA genotype in European populations reaches 40-56%.
2. Lindh JD, Holm L, Andersson ML, Rane A. ‘Influence of CYP2C9 genotype on warfarin dose requirements – a systematic review and meta-analysis’. Eur J Clin Pharmacol, 2009, 65(4), 365–75.
3. Glurich I, Burmester JK, Caldwell MD. ‘Understanding the pharmacogenetic approach to warfarin dosing’. Heart Fail Rev, 2008.