Implementing genotype-guided antithrombotic therapy.
Genotyping has the potential to improve the efficacy and safety of major antithrombotic drugs. For warfarin, the stable maintenance dose varies from 1-10 mg/day. The VKORC1 -1639G>A allele and the CYP2C9*2 and *3 alleles (cumulative frequency: 90% in Asians, 65% in Europeans and 20% in Africans), explain 45% of response variability in European and 30% in African populations. The large clinical trials COAG and EU-PACT will define the extent to which pharmacogenetic dosing affects the safety and efficacy of warfarin and coumarin derivatives. The platelet inhibitor clopidogrel requires activation by the CYP2C19 enzyme. CYP2C19*2 and *3 alleles (cumulative frequency: 20-50%) produce null enzyme activity, and their presence attenuates platelet inhibition and increases cardiovascular events. The US FDA-mandated drug labeling recognizes the relevance of genotyping in the selection and dosing of both warfarin and clopidogrel.
Seip
Richard L
RL
Genomas, Inc., 67 Jefferson Street, Hartford, CT 06106, USA.
Duconge
Jorge
J
Ruaño
Gualberto
G
D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D000077144:Clopidogrel; D003362:Cost-Benefit Analysis; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D030661:Genetic Privacy; D005838:Genotype; D006291:Health Policy; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D000068799:Prasugrel Hydrochloride; D057285:Precision Medicine; D058919:Purinergic P2 Receptor Antagonists; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology / Q000627:therapeutic use
D000925:Anticoagulants; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D013876:Thiophenes; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
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