Pharmacogenetics of Target Genes Across the Warfarin Pharmacological Pathway
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Clin Pharmacokinet 2006; 45 (12): 1189-1200 0312-5963/06/0012-1189/$39.95/0 © 2006 Adis Data Information BV. All rights reserved.
Pharmacogenetics of Target Genes Across the Warfarin Pharmacological Pathway Suman Lal,1 Srinivasa Rao Jada,1 Xiaoqiang Xiang,1 Wan-Teck Lim,2 Edmund J.D. Lee3 and Balram Chowbay1 1 2 3
National Cancer Centre, Laboratory of Clinical Pharmacology, Division of Medical Sciences, Singapore, Singapore Department of Medical Oncology, National Cancer Centre, Singapore, Singapore Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore, Singapore
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189 1. Pharmacology of Warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190 2. Warfarin Pharmacogenetic Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191 2.1 Cytochrome P450 (CYP)2C9 (CYP2C9) Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191 2.2 Clinical Implications of CYP2C9 Genotypes on Warfarin Dosage . . . . . . . . . . . . . . . . . . . . . . . . . 1193 3. Vitamin K Cycle and Warfarin Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193 3.1 Vitamin K 2,3-Epoxide Reductase complex, subunit 1 (VKORC1) Gene . . . . . . . . . . . . . . . . . . . 1193 3.2 γ-Glutamyl Carboxylase (GGCX) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195 3.3 Apolipoprotein E and Vitamin K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1196 4. Additional Pathway Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197 5. Clinical Relevance and Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197
Abstract
Warfarin is a widely prescribed anticoagulant for thromboembolic disorders and exhibits wide inter-individual differences in its pharmacodynamic effects. Warfarin exerts its anticoagulant effect by inhibiting the enzymatic activity of vitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) which regenerates reduced vitamin K as an essential cofactor for the post-translational γ-carboxylation of glutamic acid residues on coagulation factors II, VII, IX and X, and the anticoagulant proteins C, S and Z. Recent studies have shown polymorphisms in genes involved in the uptake of vitamin K (apolipoprotein E [ApoE]), reduction of vitamin K 2,3-epoxide (VKORC1), metabolism of warfar
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