Pharmacogenetics of oral anticoagulants: A basis for dose individualization

Clinical Pharmacokinetics

Volumn 47, Issue 9, 2008, Pages 565-594

  Stehle, Simone ^a   Kirchheiner, Julia ^b   Lazar, Andreas ^a   Fuhr, Uwe ^a  

^a UNIVERSITY OF COLOGNE   (Germany)

^b UNIVERSITY OF ULM   (Germany)

Author keywords

Acenocoumarol, therapeutic use; Anticoagulants, therapeutic use; Cytochrome P450; Genetic polymorphism; Pharmacogenetics; Pharmacokinetics; Phenprocoumon, therapeutic use; Vitamin K antagonists, therapeutic use; Warfarin, therapeutic use

Indexed keywords

ACENOCOUMAROL; ANTICOAGULANT AGENT; ANTIVITAMIN K; APOLIPOPROTEIN E; COUMARIN DERIVATIVE; CYTOCHROME P450 2C9; CYTOSINE; GLUTATHIONE TRANSFERASE A1; HYDROLASE; MENADIONE EPOXIDE; MICROSOMAL EPOXIDE HYDROLASE; OXIDOREDUCTASE; PHENPROCOUMON; THYMINE; VITAMIN K DEPENDENT CARBOXYLASE; VITAMIN K EPOXIDE REDUCTASE COMPLEX SUBUNIT 1; WARFARIN;

ALLELE; ANTICOAGULATION; BLEEDING; CAUCASIAN; CLINICAL TRIAL; CYP2C9 GENE; DOSE CALCULATION; DOSE RESPONSE; DRUG CLEARANCE; DRUG EFFECT; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG PROTEIN BINDING; ENZYME ACTIVITY; ETHNIC DIFFERENCE; GENE; GENETIC POLYMORPHISM; GENETIC RISK; GENOTYPE; HETEROZYGOTE; HIGH RISK POPULATION; HOMOZYGOTE; HUMAN; INTERNATIONAL NORMALIZED RATIO; LOADING DRUG DOSE; MEDICAL LITERATURE; MEDLINE; PRIORITY JOURNAL; PUBLICATION; RECURRENT DISEASE; REVIEW; SINGLE DRUG DOSE; SYSTEMATIC REVIEW; THROMBOEMBOLISM; THROMBOSIS; TREATMENT PLANNING; VKORC1 GENE;

ACENOCOUMAROL; ADMINISTRATION, ORAL; ANTICOAGULANTS; ARYL HYDROCARBON HYDROXYLASES; CLINICAL TRIALS AS TOPIC; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MIXED FUNCTION OXYGENASES; PHARMACOGENETICS; PHENPROCOUMON; WARFARIN;

EID: 49549107264     PISSN: 03125963     EISSN: 03125963     Source Type: Journal    
DOI: 10.2165/00003088-200847090-00002     Document Type: Review

References (163)

1. Hirsh J. Antithrombotic therapy in deep vein thrombosis and pulmonary embolism. Am Heart J 1992 Apr; 123 (4 Pt 2): 1115-22
2. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001 Jan; 119 (1 Suppl.): 8S-21S
3. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998 Nov; 114 (5 Suppl.): 445S-69S
4. Laupacis A, Albers G, Dalen J, et al. Antithrombotic therapy in atrial fibrillation. Chest 1995 Oct; 108 (4 Suppl.): 352S-9S
5. Stein PD, Alpert JS, Copeland J, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1995 Oct; 108 (4 Suppl.): 371S-9S
6. Latner AW. The top 200 drugs of 1999. Pharm Times 2000; 66 (4): 16-32
7. Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000 Nov; 28 (11): 1284-90
8. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993 Sep; 95 (3): 315-28
9. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996 Aug 17; 348 (9025): 423-8
10. Hummers-Pradier E, Hess S, Adham IM, et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 2003 Jul; 59 (3): 213-9
11. Tiaden JD, Wenzel E, Berthold HK, et al. Adverse reactions to anticoagulants and to antiplatelet drugs recorded by the German spontaneous reporting system. Semin Thromb Hemost 2005; 31 (4): 371-80
12. Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999 Feb 27; 353 (9154): 717-9
13. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002 Apr 3; 287 (13): 1690-8
14. Margaglione M, Colaizzo D, D'Andrea G, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000 Nov; 84 (5): 775-8
15. Ogg MS, Brennan P, Meade T, et al. CYP2C9*3 allelic variant and bleeding complications. Lancet 1999 Sep 25; 354 (9184): 1124
16. James AH, Britt RP, Raskino CL, et al. Factors affecting the maintenance dose of warfarin. J Clin Pathol 1992 Aug; 45 (8): 704-6
17. Visser LE, Trienekens PH, De Smet PA, et al. Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genomics 2005 Feb; 15 (2): 69-74
18. Hirsh J, Dalen JE, Deykin D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1995 Oct; 108 (4 Suppl.): 231S-46S
19. Linder MW. Genetic mechanisms for hypersensitivity and resistance to the anticoagulant warfarin. Clin Chim Acta 2001 Jun; 308 (1-2): 9-15
20. Rost S, Fregin A, Koch D, et al. Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol 2004 Aug; 126 (4): 546-9
21. Sadler JE. Medicine: K is for koagulation. Nature 2004 Feb 5; 427 (6974): 493-4
22. Fasco MJ, Principe LM. R- and S-warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. J Biol Chem 1982 May 10; 257 (9): 4894-901
23. de Vries JX, Simon M, Volker U, et al. Comparative plasma disposition and anticoagulant activities of racemic phenprocoumon and its metabolites in rats. Haemostasis 1993; 23 (1): 13-8
24. He M, Korzekwa KR, Jones JP, et al. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys 1999 Dec 1; 372 (1): 16-28
25. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73 (1): 67-74
26. Alberio L. Oral anticoagulation with vitamin K antagonists [in German]. Ther Umsch 2003 Jan; 60 (1): 5-9
27. Pyorala K, Jussila J, Mustala O, et al. Absorption of warfarin from the stomach and small intestine. Scand J Gastroenterol 1971; 9 Suppl.: 95-103
28. de Vries JX, Volker U. Determination of the plasma protein binding of the coumarin anticoagulants phenprocoumon and its metabolites, warfarin and acenocoumarol, by ultrafiltration and high-performance liquid chromatography. J Chromatogr 1990 Aug 3; 529 (2): 479-85
29. Jahnchen E, Meinertz T, Gilfrich HJ, et al. The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther 1976 Sep; 20 (3): 342-9
30. Hemker HC, Frank HL. The mechanism of action of oral anticoagulants and its consequences for the practice of oral anticoagulation. Haemostasis 1985; 15 (4): 263-70
31. Thijssen HH, Hamulyak K, Willigers H. 4-Hydroxycoumarin oral anticoagulants: pharmacokinetics-response relationship. Thromb Haemost 1988 Aug 30; 60 (1): 35-8
32. Ufer M, Svensson JO, Krausz KW, et al. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004 May; 60 (3): 173-82
33. Pohl LR, Haddock RE, Trager WF. Biotransformation of phenprocoumon in the rat. J Med Chem 1975 May; 18 (5): 519-23
34. Stirling Y, Howarth DJ, Stockley R, et al. Comparison of the bioavailabilities and anticoagulant activities of two warfarin formulations. Br J Haematol 1982 May; 51 (1): 37-46
35. Yacobi A, Udall JA, Levy G. Intrasubject variation of warfarin binding to protein in serum of patients with cardiovascular disease. Clin Pharmacol Ther 1976 Sep; 20 (3): 300-3
36. Yacobi A, Udall JA, Levy G. Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect. Clin Pharmacol Ther 1976 May; 19 (5 Pt 1): 552-8
37. Chan E, McLachlan AJ, Pegg M, et al. Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol 1994 Jun; 37 (6): 563-9
38. Hewick DS, McEwen J. Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 1973 Jun; 25 (6): 458-65
39. Lewis RJ, Trager WF. Warfarin metabolism in man: identification of metabolites in urine. J Clin Invest 1970 May; 49 (5): 907-13
40. Lewis RJ, Trager WF, Chan KK, et al. Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 1974 Jun; 53 (6): 1607-17
41. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992 Jan-Feb; 5 (1): 54-9
42. Toon S, Low LK, Gibaldi M, et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986 Jan; 39 (1): 15-24
43. Kelly JG, O'Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 1979 Jan-Feb; 4 (1): 1-15
44. Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44 (12): 1227-46
45. Trager WF, Lewis RJ, Garland WA. Mass spectral analysis in the identification of human metabolites of warfarin. J Med Chem 1970 Nov; 13 (6): 1196-204
46. Kaminsky LS, de Morais SM, Faletto MB, et al. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 1993 Feb; 43 (2): 234-9
47. Wienkers LC, Steenwyk RC, Sanders PE, et al. Biotransformation of tirilazad in human: 1. Cytochrome P450 3A-mediated hydroxylation of tirilazad mesylate in human liver microsomes. J Pharmacol Exp Ther 1996 May; 277 (2): 982-90
48. Zhang ZY, Kerr J, Wexler RS, et al. Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation. Thromb Res 1997 Nov 15; 88 (4): 389-98
49. Hermans JJ, Thijssen HH. The in vitro ketone reduction of warfarin and analogues: substrate stereoselectivity, product stereoselectivity and species differences. Biochem Pharmacol 1989 Oct 1; 38 (19): 3365-70
50. Kaminsky LS. Warfarin as a probe of cytochromes P-450 function. Drug Metab Rev 1989; 20 (2-4): 479-87
51. Dieterle W, Faigle JW, Montigel C, et al. Biotransformation and pharmacokinetics of acenocoumarol (Sintrom) in man. Eur J Clin Pharmacol 1977; 11 (5): 367-75
52. Thijssen HH, Drittij MJ, Vervoort LM, et al. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 2001 Sep; 70 (3): 292-8
53. Hermans JJ, Thijssen HH. Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4′-nitrowarfarin (acenocoumarol). Xenobiotica 1991 Mar; 21 (3): 295-307
54. Hermans JJ, Thijssen HH. Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics. Br J Pharmacol 1993 Sep; 110 (1): 482-90
55. Thijssen HH, Janssen GM, Baars LG. Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol. Eur J Clin Pharmacol 1986; 30 (5): 619-23
56. Toon S, Heimark LD, Trager WF, et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985 Oct; 74 (10): 1037-40
57. Kammerer B, Kahlich R, Ufer M, et al. Stereospecific pharmacokinetic characterisation of phenprocoumon metabolites, and mass-spectrometric identification of two novel metabolites in human plasma and liver microsomes. Anal Bioanal Chem 2005 Nov; 383 (6): 909-17
58. Ufer M, Kammerer B, Kahlich R, et al. Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo. Xenobiotica 2004 Sep; 34 (9): 847-59
59. de Vries JX, Raedsch R, Volker U, et al. Biliary excretion of phenprocoumon and metabolites. Eur J Clin Pharmacol 1988; 35 (4): 433-6
60. Edelbroek PM, van Kempen GM, Hessing TJ, et al. Analysis of phenprocoumon and its hydroxylated and conjugated metabolites in human urine by high-performance liquid chromatography after solid-phase extraction. J Chromatogr 1990 Sep 14; 530 (2): 347-58
61. Heni N, Glogner P. Pharmacokinetics of phenprocoumon in man investigated using a gas chromatographic method of drug analysis. Naunyn Schmiedebergs Arch Pharmacol 1976 May; 293 (2): 183-6
62. Heimark LD, Toon S, Gibaldi M, et al. The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans. Clin Pharmacol Ther 1987 Sep; 42 (3): 312-9
63. zu Schwabedissen CM, Mevissen V, Schmitz F, et al. Obesity is associated with a slower response to initial phenprocoumon therapy whereas CYP2C9 genotypes are not. Eur J Clin Pharmacol 2006 Sep; 62 (9): 713-20
64. Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006 Dec; 22 (3): 191-7
65. Herman D, Locatelli I, Grabnar I, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J 2005; 5 (3): 193-202
66. Kimura R, Miyashita K, Kokubo Y, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007; 120 (2): 181-6
67. Millican E, Jacobsen-Lenzini PA, Milligan PE, et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood 2007 Sep 1; 110 (5): 1511-5
68. Peyvandi F, Spreafico M, Siboni SM, et al. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy. Clin Pharmacol Ther 2004 Mar; 75 (3): 198-203
69. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005 Oct 1; 106 (7): 2329-33
70. Scordo MG, Pengo V, Spina E, et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002 Dec; 72 (6): 702-10
71. Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000 Sep 1; 96 (5): 1816-9
72. Michaud V, Vanier MC, Brouillette D, et al. Combination of phenotype assessments and CYP2C9-VKORC1 polymorphisms in the determination of warfarin dose requirements in heavily medicated patients. Clin Pharmacol Ther 2008 May; 83 (5): 740-8
73. Wadelius M, Sorlin K, Wallerman O, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004; 4 (1): 40-8
74. Miao L, Yang J, Huang C, et al. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol 2007 Dec; 63 (12): 1135-41
75. Momary KM, Shapiro NL, Viana MA, et al. Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics 2007 Nov; 8 (11): 1535-44
76. Lindh JD, Lundgren S, Holm L, et al. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 2005 Nov; 78 (5): 540-50
77. Steward DJ, Haining RL, Henne KR, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997 Oct; 7 (5): 361-7
78. Schalekamp T, Brasse BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006 Jul; 80 (1): 13-22
79. Mark L, Marki-Zay J, Fodor L, et al. Cytochrome P450 2C9 polymorphism and acenocoumarol therapy. Kardiol Pol 2006 Apr; 64 (4): 397-402; discussion 403-4
80. Tassies D, Freire C, Pijoan J, et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002 Nov; 87 (11): 1185-91
81. Visser LE, van Vliet M, van Schaik RH, et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004 Jan; 14 (1): 27-33
82. Schalekamp T, Brasse BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007 Feb; 81 (2): 185-93
83. Schalekamp T, Oosterhof M, van Meegen E, et al. Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther 2004 Nov; 76 (5): 409-17
84. Schelleman H, Chen Z, Kealey C, et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 2007 May; 81 (5): 742-7
85. Herman D, Peternel P, Stegnar M, et al. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006 May; 95 (5): 782-7
86. D'Andrea G, D'Ambrosio RL, Di Perna P, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005 Jan 15; 105 (2): 645-9
87. Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem 2007 Jul; 53 (7): 1199-205
88. Borgiani P, Ciccacci C, Forte V, et al. Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics 2007 Nov; 8 (11): 1545-50
89. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999 Oct 15; 286 (5439): 487-91
90. Yasar U, Eliasson E, Dahl ML, et al. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999 Jan 27; 254 (3): 628-31
91. Xie HG, Prasad HC, Kim RB, et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002 Nov 18; 54 (10): 1257-70
92. Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001 Dec; 11 (9): 803-8
93. Yasar U, Aklillu E, Canaparo R, et al. Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations. Eur J Clin Pharmacol 2002 Nov; 58 (8): 555-8
94. Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics 1997 Jun; 7 (3): 203-10
95. Haining RL, Hunter AP, Veronese ME, et al. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996 Sep 15; 333 (2): 447-58
96. Rettie AE, Wienkers LC, Gonzalez FJ, et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994 Feb; 4 (1): 39-42
97. Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther 1974 Apr; 15 (4): 424-30
98. Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40 (8): 587-603
99. Loebstein R, Yonath H, Peleg D, et al. Interindividual variability in sensitivity to warfarin: nature or nurture? Clin Pharmacol Ther 2001 Aug; 70 (2): 159-64
100. Takahashi H, Kashima T, Nomizo Y, et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 1998 May; 63 (5): 519-28
101. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 2003; 3 (4): 202-14
102. Freeman BD, Zehnbauer BA, McGrath S, et al. Cytochrome P450 polymorphisms are associated with reduced warfarin dose. Surgery 2000 Aug; 128 (2): 281-5
103. Kohnke H, Sorlin K, Granath G, et al. Warfarin dose related to apolipoprotein E (APOE) genotype. Eur J Clin Pharmacol 2005 Jul; 61 (5-6): 381-8
104. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005 Feb; 7 (2): 97-104
105. Bloch A, Ben-Chetrit E, Muszkat M, et al. Major bleeding caused by warfarin in a genetically susceptible patient. Pharmacotherapy 2002 Jan; 22 (1): 97-101
106. Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008 Feb; 83 (2): 312-21
107. Takahashi H, Wilkinson GR, Padrini R, et al. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004 May; 75 (5): 376-80
108. Thijssen HH, Ritzen B. Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther 2003 Jul; 74 (1): 61-8
109. Visser LE, van Schaik RH, van Vliet M, et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004 Jul; 92 (1): 61-6
110. Mark L, Marki-Zay J, Paragh G, et al. Retrospective analyses of acenocoumarol doses and bleeding complications in patients with wild type or variant cytochrome P450 CYP2C9 alleles. Thromb Haemost 2005 Feb; 93 (2): 396-7
111. Kirchheiner J, Ufer M, Walter EC, et al. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics 2004 Jan; 14 (1): 19-26
112. Pauli RM, Lian JB, Mosher DF, et al. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 1987 Oct; 41 (4): 566-83
113. Cain D, Hutson SM, Wallin R. Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem 1997 Nov 14; 272 (46): 29068-75
114. Reitsma PH, van der Heijden JF, Groot AP, et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005 Oct; 2 (10): e312
115. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005 Jun 2; 352 (22): 2285-93
116. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5 (4): 262-70
117. Osman A, Enstrom C, Arbring K, et al. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost 2006 Aug; 4 (8): 1723-9
118. Loebstein R, Dvoskin I, Halkin H, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007 Mar 15; 109 (6): 2477-80
119. Obayashi K, Nakamura K, Kawana J, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006 Aug; 80 (2): 169-78
120. Veenstra DL, You JH, Rieder MJ, et al. Association of vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 2005 Oct; 15 (10): 687-91
121. Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006 Feb; 16 (2): 101-10
122. Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005 Oct; 94 (4): 773-9
123. Yuan HY, Chen JJ, Lee MT, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005 Jul 1; 14 (13): 1745-51
124. Bodin L, Verstuyft C, Tregouet DA, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005 Jul 1; 106 (1): 135-40
125. Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 Feb 5; 427 (6974): 537-41
126. Harrington DJ, Underwood S, Morse C, et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005 Jan; 93 (1): 23-6
127. Tham LS, Goh BC, Nafziger A, et al. A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006 Oct; 80 (4): 346-55
128. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 2007 Apr; 7 (2): 99-111
129. Cain D, Hutson SM, Wallin R. Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver. Thromb Haemost 1998 Jul; 80 (1): 128-33
130. Bredschneider M, Klein K, Murdter TE, et al. Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation. Clin Pharmacol Ther 2002 Jun; 71 (6): 479-87
131. Morel F, Rauch C, Coles B, et al. The human glutathione transferase alpha locus: genomic organization of the gene cluster and functional characterization of the genetic polymorphism in the hGSTA1 promoter. Pharmacogenetics 2002 Jun; 12 (4): 277-86
132. Loebstein R, Vecsler M, Kurnik D, et al. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Clin Pharmacol Ther 2005 May; 77 (5): 365-72
133. Hassett C, Aicher L, Sidhu JS, et al. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet 1994 Mar; 3 (3): 421-8
134. Omiecinski CJ, Hassett C, Hosagrahara V. Epoxide hydrolase: polymorphism and role in toxicology. Toxicol Lett 2000 Mar 15; 112-113: 365-70
135. Hassett C, Lin J, Carty CL, et al. Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression. Arch Biochem Biophys 1997 Jan 15; 337 (2): 275-83
136. Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc 1997 Nov; 56 (3): 915-37
137. Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost 2004 Dec; 2 (12): 2118-32
138. Saupe J, Shearer MJ, Kohlmeier M. Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis. Am J Clin Nutr 1993 Aug; 58 (2): 204-8
139. Kohlmeier M, Salomon A, Saupe J, et al. Transport of vitamin K to bone in humans. J Nutr 1996 Apr; 126 (4 Suppl.): 1192S-6S
140. Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007 Mar; 121 (1): 23-34
141. Sconce EA, Daly AK, Khan TI, et al. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006 Aug; 16 (8): 609-11
142. Lal S, Sandanaraj E, Jada SR, et al. Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients. Br J Clin Pharmacol 2008 Feb; 65 (2): 260-4
143. Kuo WL, Stafford DW, Cruces J, et al. Chromosomal localization of the gamma-glutamyl carboxylase gene at 2p12. Genomics 1995 Feb 10; 25 (3): 746-8
144. Lingenfelter SE, Berkner KL. Isolation of the human gamma-carboxylase and a gamma-carboxylase-associated protein from factor IX-expressing mammalian cells. Biochemistry 1996 Jun 25; 35 (25): 8234-43
145. Suttie JW, Canfield LM, Shah DV. Microsomal vitamin K-dependent carboxylase. Methods Enzymol 1980; 67: 180-5
146. Wu SM, Stafford DW, Frazier LD, et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood 1997 Jun 1; 89 (11): 4058-62
147. Rieder MJ, Reiner AP, Rettie AE. Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost 2007 Nov; 5 (11): 2227-34
148. Hylek EM, Regan S, Go AS, et al. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001 Sep 18; 135 (6): 393-400
149. Hamberg AK, Dahl ML, Barban M, et al. A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 2007 Apr; 81 (4): 529-38
150. Almog S, Shafran N, Halkin H, et al. Mechanism of warfarin potentiation by amiodarone: dose- and concentration-dependent inhibition of warfarin elimination. Eur J Clin Pharmacol 1985; 28 (3): 257-61
151. Transon C, Leemann T, Vogt N, et al. In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther 1995 Oct; 58 (4): 412-7
152. Hemeryck A, De Vriendt C, Belpaire FM. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 1999 Feb; 54 (12): 947-51
153. Ahmad S. Lovastatin: warfarin interaction. Arch Intern Med 1990 Nov; 150 (11): 2407
154. Chan E, McLachlan A, O'Reilly R, et al. Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1994 Sep; 56 (3): 286-94
155. Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003 Aug; 3 (3): 221-30
156. Madabushi R, Frank B, Drewelow B, et al. Hyperforin in St John's wort drug interactions. Eur J Clin Pharmacol 2006 Mar; 62 (3): 225-33
157. Harder S, Thurmann P. Clinically important drug interactions with anticoagulants: an update. Clin Pharmacokinet 1996 Jun; 30 (6): 416-44
158. Lubetsky A, Dekel-Stern E, Chetrit A, et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999 Mar; 81 (3): 396-9
159. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drugs and food. Ann Intern Med 1994 Nov 1; 121 (9): 676-83
160. Zhao F, Loke C, Rankin SC, et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther 2004 Sep; 76 (3): 210-9
161. Kuehn BM. Health agencies update: warfarin label update. JAMA 2007 Sep 26; 298 (12): 1389
162. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007 Nov 27; 116 (22): 2563-70
163. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008 Mar; 83 (3): 460-70